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<p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 1 of 67</p><p>The integrated brain network that</p><p>controlsrespiration</p><p>Friedrich Krohn1, Manuele Novello1, Ruben S van der Giessen2,</p><p>Chris I De Zeeuw1,3*, Johan JM Pel1*, Laurens WJ Bosman1*</p><p>1Department of Neuroscience, Erasmus MC, Rotterdam, Netherlands; 2Department</p><p>of Neurology, Erasmus MC, Rotterdam, Netherlands; 3Netherlands Institute for</p><p>Neuroscience, Royal Academy of Arts and Sciences, Amsterdam, Netherlands</p><p>Abstract Respiration is a brain function on which our lives essentially depend. Control of respi-</p><p>ration ensures that the frequency and depth of breathing adapt continuously to metabolic needs. In</p><p>addition, the respiratory control network of the brain has to organize muscular synergies that inte-</p><p>grate ventilation with posture and body movement. Finally, respiration is coupled to cardiovascular</p><p>function and emotion. Here, we argue that the brain can handle this all by integrating a brainstem</p><p>central pattern generator circuit in a larger network that also comprises the cerebellum. Although</p><p>currently not generally recognized as a respiratory control center, the cerebellum is well known</p><p>for its coordinating and modulating role in motor behavior, as well as for its role in the autonomic</p><p>nervous system. In this review, we discuss the role of brain regions involved in the control of respira-</p><p>tion, and their anatomical and functional interactions. We discuss how sensory feedback can result in</p><p>adaptation of respiration, and how these mechanisms can be compromised by various neurological</p><p>and psychological disorders. Finally, we demonstrate how the respiratory pattern generators are part</p><p>of a larger and integrated network of respiratory brain regions.</p><p>Introduction</p><p>From the first cry to the last gasp, the respiratory system should never fail to supply sufficient oxygen</p><p>to meet metabolic demands during every possible event throughout life (Del Negro etal., 2018). The</p><p>respiratory pattern is not only determined by physical activity, but also reflects the emotional state,</p><p>and volitional control of respiration can be used to alter affection and reduce stress (Suess etal.,</p><p>1980; Philippot etal., 2002; Arch and Craske, 2006; Seppälä etal., 2014; Szulczewski, 2019).</p><p>Indeed, multiple behaviors, such as swimming, playing musical instruments, parturition, or medita-</p><p>tion depend on precise respiratory control (Brown and Gerbarg, 2009; Jakovljevic and McConnell,</p><p>2009; Bartlett and Leiter, 2012; Holstege, 2014; Sakaguchi and Aiba, 2016), and for many sports</p><p>and arts, it is often the control of respiration that separates mediocre from top performance (Mahler</p><p>etal., 1991; Phillips and Aitchison, 1997; Laczika etal., 2013; Salomoni etal., 2016). Thus, indeed,</p><p>respiratory control affects all aspects of life.</p><p>Although control over respiration can be voluntary, most of it is subconscious, even during volun-</p><p>tary respiration. In this review, we discuss the integrated network of brain regions most involved in</p><p>the control of respiration, their connections, and possible clinical consequences of their pathology.</p><p>Throughout, we discuss how respiratory control and other motor and non- motor systems interact.</p><p>Respiratory muscles and their motor neurons</p><p>Despite their vast differences in body size and ecological niches, mammals possess similar basic</p><p>mechanics of ventilation, with some variations between species or sexes (Carvalho and Gonçalves,</p><p>2011; Torres- Tamayo etal., 2018). Both lung and tidal volumes scale linearly with body weight, and</p><p>REVIEW ARTICLE</p><p>*For correspondence:</p><p>c.dezeeuw@erasmusmc.nl</p><p>(CIDZ);</p><p>j.pel@erasmusmc.nl (JJMP);</p><p>l.bosman@erasmusmc.nl (LWJB)</p><p>Competing interest: The authors</p><p>declare that no competing</p><p>interests exist.</p><p>Funding: See page 35</p><p>Received: 03 October 2022</p><p>Accepted: 29 January 2023</p><p>Published: 08 March 2023</p><p>Reviewing Editor: Jeannie Chin,</p><p>Baylor College of Medicine,</p><p>United States</p><p>Copyright Krohn etal. This</p><p>article is distributed under the</p><p>terms of the Creative Commons</p><p>Attribution License, which</p><p>permits unrestricted use and</p><p>redistribution provided that the</p><p>original author and source are</p><p>credited.</p><p>https://en.wikipedia.org/wiki/Open_access</p><p>https://creativecommons.org/</p><p>https://elifesciences.org/?utm_source=pdf&utm_medium=article-pdf&utm_campaign=PDF_tracking</p><p>https://doi.org/10.7554/eLife.83654</p><p>mailto:c.dezeeuw@erasmusmc.nl</p><p>mailto:j.pel@erasmusmc.nl</p><p>mailto:l.bosman@erasmusmc.nl</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>http://creativecommons.org/licenses/by/4.0/</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 2 of 67</p><p>the higher metabolic rate of smaller mammals is accounted for by a faster respiratory rate (Stahl,</p><p>1967; Boggs and Tenney, 1984). The force required for inspiration is delivered by so- called pump</p><p>muscles that expand the rib cage. The diaphragm and external intercostal muscles are the most prom-</p><p>inent inspiratory pump muscles, but also parasternal intercostal, sternocleidomastoid and scalene</p><p>muscles can act as such (De Troyer and Estenne, 1984; De Troyer etal., 1998; De Troyer etal.,</p><p>2005; Torres- Tamayo etal., 2018; Welch etal., 2019; LoMauro and Aliverti, 2021). During active</p><p>expiration, expiratory pump muscles, in particular the internal intercostal and abdominal muscles, are</p><p>active (De Troyer etal., 2005; Mortola, 2013; Welch etal., 2019). The diaphragm is under control</p><p>of motor neurons in the phrenic nucleus located in the anterior ramus of the third to sixth cervical</p><p>vertebrae (Wertheimer, 1886; Hollinshead and Keswani, 1956; Wu etal., 2017). The intercostal and</p><p>abdominal muscles are innervated from the thoracic spinal cord (Figure1A–C).</p><p>Valve muscles regulate the air flow by adjusting the resistance of the upper airways. Activity of</p><p>the facial nucleus can lead to opening of the nasal valve, via the dilator naris anterior muscle and the</p><p>alar part of the nasal muscle (van Dishoeck, 1937; Strohl, 1985; Vaiman etal., 2003). Contractions</p><p>of these muscles do not only facilitate inspiration, but can also relate to sniffing (Welker, 1964). Just</p><p>before the start of inspiration, motor neurons of the hypoglossal nucleus activate tongue muscles,</p><p>reducing collapsibility of the pharynx (Fuller etal., 1999; Gestreau etal., 2005). Indeed, tongue</p><p>deformation, for example as a consequence of excessive fat depositions in obesity, can be related to</p><p>obstructive sleep apnea (Lowe etal., 1986; Kim etal., 2014; Yu etal., 2021). Activation of the trigem-</p><p>inal motor nucleus can contribute to jaw movements (Mong etal., 1988). Finally, contractions of the</p><p>larynx muscles show a bimodal pattern; initially, they are dilated to allow airflow into the lungs, while</p><p>at the end of inspiration these muscles contract to reduce the outflow of air, prolonging the period</p><p>of gas exchange (Gesell and White, 1938; Gautier etal., 1973; Insalaco etal., 1991; Hutchison</p><p>etal., 1993; Amis etal., 1995; Dutschmann etal., 2014). Laryngeal constriction is controlled by the</p><p>nucleus ambiguus via the vagus nerve (Dutschmann etal., 2014). The nucleus ambiguus houses also</p><p>motor neurons controlling swallowing, the control of which is strongly coupled to that of respiration</p><p>(McFarland and Lund, 1993; Moore etal., 2014).</p><p>Respiratory muscles typically serve multiple functions. Rib cage muscles, for instance, control</p><p>both respiration and arm movements, so that locomotion and respiration are tightly coupled during</p><p>quadrupedal locomotion. Indeed, one could argue that the change from quadrupedal to bipedal loco-</p><p>motion during hominid evolution paved the way for the intricate breathing control required for human</p><p>speech (Carrier, 1984; MacLarnon and Hewitt, 1999).</p><p>Functional anatomy of respiratory control</p><p>Below, we describe the brain areas most involved in subconscious control of respiration, and their</p><p>main connections. Most of these pathways are bilateral, but ipsi- and contralateral projections can</p><p>al., 2011; McDe-</p><p>vitt etal., 2014). Descending projections target the hypoglossal, trigeminal and facial motor nuclei</p><p>(Li etal., 1993; Guo etal., 2020), retrotrapezoid nucleus (Rosin etal., 2006), locus coeruleus (Luppi</p><p>etal., 1995; Schwarz etal., 2015), periaqueductal gray (Vertes, 1991), and PPTg (Vertes, 1991;</p><p>Steininger etal., 1992; Figure6B).</p><p>The dorsal raphe nucleus receives input from many areas, with relatively dense projections orig-</p><p>inating in the cerebral cortex, lateral, paraventricular and dorsomedial hypothalamus, bed nucleus</p><p>of the stria terminalis, central amygdala, periaqueductal gray, lateral and medial parabrachial nuclei,</p><p>Kölliker- Fuse nucleus, NTS, locus coeruleus, and vestibular nuclei (Jones and Yang, 1985; Peyron</p><p>etal., 1998a; Pollak Dorocic etal., 2014; Weissbourd etal., 2014; Peyron etal., 2018; Shi etal.,</p><p>2021). In addition, also the cerebellar nuclei project to the dorsal raphe nucleus, but this projection</p><p>seems to be relatively sparse (Teune etal., 2000; Weissbourd etal., 2014).</p><p>The caudal, or medullary, raphe nuclei can also directly affect respiration (Lalley, 1986; Ptak etal.,</p><p>2009; Depuy etal., 2011; Sabino etal., 2021). The caudal raphe nuclei exist of the raphe magnus,</p><p>raphe obscurus, and raphe pallidus, and contain serotonergic, non- serotonergic and mixed neurons</p><p>(Pilowsky, 2014; Figure6A). Accordingly, neural responses of neurons in the caudal raphe are hetero-</p><p>geneous and hypercapnic acidosis can activate some, and inhibit other neurons of the caudal raphe</p><p>(Richerson, 1995; Wang et al., 1998), the former category comprising serotonergic neurons, the</p><p>latter not (Wang etal., 2001; Taylor etal., 2005).</p><p>Egr2- Pet1- expressing serotonergic neurons of the raphe magnus mediate the respiratory CO2</p><p>chemoreflex (Brust etal., 2014). These chemoreceptor neurons target predominantly other chemo-</p><p>receptor areas in the brainstem: the retrotrapezoid nucleus, NTS, locus coeruleus, pre- Bötzinger</p><p>complex and medial parabrachial nucleus (Brust et al., 2014). Tac1- Pet1- expressing serotonergic</p><p>neurons of the raphe obscurus do not express chemoreceptor properties themselves, but are most</p><p>likely downstream of Egr2- Pet1 neurons and preferentially innervate motor nuclei, including the</p><p>phrenic, facial, trigeminal, hypoglossal, and ambiguus nucleus, but also the pre- Bötzinger complex</p><p>and NTS (Hennessy etal., 2017).</p><p>Lateral hypothalamus</p><p>Orexinergic neurons of the lateral hypothalamus are the only neurons of the diencephalon with central</p><p>chemoreceptor properties (Williams etal., 2007; Song etal., 2012b; Li etal., 2013; Fukushi etal.,</p><p>2019; Wang etal., 2021). Orexins, neuropeptides exclusively produced by the lateral and posterior</p><p>hypothalamus, are distributed widely throughout the brain and promote wakefulness (de Lecea etal.,</p><p>1998; Peyron etal., 1998b; Hagan etal., 1999; Adamantidis etal., 2007; Berteotti etal., 2021).</p><p>The activity of orexinergic neurons is largely restricted to the awake state (Mileykovskiy etal., 2005),</p><p>and dysfunction of the orexinergic system can cause narcolepsy (Thannickal etal., 2000; Bassetti</p><p>etal., 2019; Berteotti etal., 2021).</p><p>Orexins can also mediate respiratory chemoreflex responses and increase the tidal volume (Young</p><p>etal., 2005; Zhang etal., 2005; Deng etal., 2007). To this end, orexinergic fibers innervate the</p><p>they occur preferably just after the onset of expiration (downward phase of the blue trace). Simple spike firing is increased during the last phase of</p><p>expiration, as illustrated by their instantaneous frequency (magenta curve). The duration of this fragment is 3.6s. (D) For this Purkinje cell, the simple</p><p>spike frequency is upregulated at the last phase of respiration, compared to the expected frequency (grey circle). 0=start inspiration. (E) Optogenetic</p><p>stimulation of Purkinje cells in the lateral cerebellum can shorten the interval until the next inspiration. (F) In the absence of excitatory output of</p><p>the cerebellar nuclei, in the Atoh1- En1/2mouse model for cerebellar neuropathology, the respiratory cycle is more regular than in control mice, as</p><p>quantified by the local coefficient of variation (CV2). fMRI scans indicate that specific brain regions, including the cerebellum, are activated during</p><p>respiratory challenges: (G) Increasing respiratory resistance. (H) Hypoxia (13% oxygen for 1min). (I) Actively slowed breathing. (J) During breath holding,</p><p>the cerebellum is not activated. * p<0.05 Scaling of activity levels in G: –6.7 to –3.1 (blue colors) and+3.1to+8.5 (red colors); in H- J: 0–15. Panels C and</p><p>D are modified from Figure 1 from Romano etal., 2020, E from Figure 6 from Romano etal., 2020, F from Figure 4 from Taylor etal., 2022, and H</p><p>and I from Figure 4 from Critchley etal., 2015.</p><p>© 2013, Elsevier. Panel G is reproduced from Figure 2 from Raux etal., 2013, with permission from Elsevier; this panel is not covered by the CC- BY</p><p>4.0 license and further reproduction of these panels would need permission from the copyright holder.</p><p>© 2008, Elsevier. Panel J is reproduced from Figure 4 from McKay etal., 2008, with permission from Elsevier; this panel is not covered by the CC- BY</p><p>4.0 license and further reproduction of these panels would need permission from the copyright holder.</p><p>Figure 6 continued</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 19 of 67</p><p>phrenic (Young etal., 2005) and hypoglossal nuclei (Fung etal., 2001; Guo etal., 2020). Other</p><p>targets include the pre- Bötzinger complex (Young et al., 2005; Yang et al., 2020; Trevizan- Baú</p><p>etal., 2021a), Kölliker- Fuse nucleus (Peyron etal., 1998b; Yokota etal., 2016; Trevizan- Baú etal.,</p><p>2021a), retrotrapezoid nucleus (Rosin etal., 2006), NTS (Peyron etal., 1998b; Gasparini etal.,</p><p>2020), locus coeruleus (Luppi et al., 1995; Peyron et al., 1998b; Hagan et al., 1999; Schwarz</p><p>etal., 2015), dorsal and caudal raphe nuclei (Lee etal., 2003; Lee etal., 2005; Ogawa etal., 2014;</p><p>Weissbourd etal., 2014), bed nucleus of the stria terminalis (Shin etal., 2008; Ni etal., 2016),</p><p>central amygdala (Peyron etal., 1998b; Fu etal., 2020), periaqueductal gray (Peyron etal., 1998b;</p><p>Trevizan- Baú etal., 2021a), and PPTg (Semba and Fibiger, 1992; Steininger etal., 1992). There is</p><p>also widespread innervation of the cerebellar cortex and nuclei, in particular of the fastigial nucleus</p><p>(Dietrichs, 1984; Ciriello and Caverson, 2014; Çavdar etal., 2018a).</p><p>Orexinergic cells of the lateral hypothalamus receive input from other areas of the hypothalamus,</p><p>including the paraventricular and dorsomedial nuclei, and from the bed nucleus of the stria terminalis,</p><p>central amygdala, periaqueductal gray, dorsal raphe nucleus, and lateral parabrachial nucleus (Yoshida</p><p>etal., 2006; Arima etal., 2019). Other studies revealed input from the pre- Bötzinger complex (Yang</p><p>and Feldman, 2018), NTS (McGovern et al., 2015b; Kawai, 2018), locus coeruleus (Jones and</p><p>Moore, 1977), medial parabrachial nucleus (Saper and Loewy, 1980; Fulwiler and Saper, 1984;</p><p>Moga etal., 1990; Bianchi etal., 1998), PPTg (Woolf and Butcher, 1986), cerebellar interposed</p><p>nucleus (Lu etal., 2015), and cerebellar dentate nucleus (Teune etal., 2000).</p><p>Fastigial nucleus</p><p>Electrical or chemical stimulation of the rostral part of the cerebellar fastigial nucleus can affect the</p><p>respiratory pattern (Bassal and Bianchi, 1982; Lutherer and Williams, 1986; Williams etal., 1989;</p><p>Xu and Frazier, 1995; Xu and Frazier, 2000; Xu etal., 2001b; Xu and Frazier, 2002; Hernandez</p><p>etal., 2004). Furthermore, bilateral lesions of the fastigial nucleus suppressed spontaneous breathing</p><p>in anesthetized cats (Williams etal., 1986). This effect was likely to be specific, as bilateral lesions of</p><p>the cerebellar dentate nuclei had no impact of spontaneous breathing in that same study. An impact</p><p>of anesthesia cannot be excluded, though,</p><p>as this result could not be reproduced in awake goats</p><p>(Martino et al., 2007). In contrast, the latter study describes a reduction in hypercapnia- induced</p><p>increases in ventilation following bilateral lesioning of the fastigial nucleus, suggesting that the impact</p><p>of the fastigial nucleus becomes especially apparent during periods with increased pCO2. Neural</p><p>recordings demonstrated activity patterns in phase with respiration at rest, but in particular during</p><p>respiratory challenges such as tracheal occlusion, bilateral carotid occlusion, or injection of sodium</p><p>cyanide (Lutherer etal., 1989; Xu and Frazier, 1997; Xu and Frazier, 2002; Lu etal., 2013). Thus,</p><p>the evidence converges on a role for the fastigial nucleus in mediating ventilatory responses to hyper-</p><p>capnia. The other two cerebellar nuclei lack the chemoreceptor abilities of the fastigial nucleus (Xu</p><p>etal., 2001a; Xu and Frazier, 2002), and putative other roles of the interposed and dentate nuclei in</p><p>respiratory control have not been extensively studied. However, electrical stimulation of these nuclei</p><p>seemed to promote expiration (Farber, 1987; Huang etal., 1993), indicating a more widespread</p><p>involvement of the cerebellum in respiratory control. The connections to and from the fastigial nucleus</p><p>are described in the section on the cerebellum.</p><p>Other sensory areas</p><p>Paratrigeminal nucleus</p><p>The NTS and the paratrigeminal nucleus together form the main entrances of vagal sensory input, and</p><p>the paratrigeminal nucleus receives mainly input from the proximal airways via the jugular ganglion</p><p>(Driessen et al., 2015; McGovern et al., 2015a; McGovern et al., 2015b). The paratrigeminal</p><p>nucleus also receives primary sensory input from the trigeminal, glossopharyngeal and lingual nerves,</p><p>and from the upper cervical cord (Saxon and Hopkins, 2006; Panneton etal., 2017; Driessen, 2019).</p><p>The strongest projections from the paratrigeminal nucleus target the NTS and the lateral and</p><p>medial parabrachial nucleus, often involving collateral projections (Menétrey etal., 1987; Saxon and</p><p>Hopkins, 1998; Caous etal., 2001; de Sousa Buck etal., 2001; McGovern etal., 2015b; Driessen</p><p>etal., 2018; Hashimoto etal., 2018). Other targets are the Kölliker- Fuse nucleus, ambiguus nucleus,</p><p>periaqueductal gray, spinal trigeminal nucleus, and inferior olive (Caous etal., 2001; de Sousa Buck</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 20 of 67</p><p>etal., 2001; McGovern etal., 2015b; Driessen etal., 2018). A projection to the cerebellum has</p><p>been described (Somana and Walberg, 1979b), but this has later been questioned (Menétrey etal.,</p><p>1987).</p><p>Spinal trigeminal nucleus</p><p>The trigeminal nerve conveys sensory input from the face and terminates in the sensory trigeminal</p><p>nuclei that consist of a primary and a spinal nucleus. The spinal nucleus appears particularly relevant</p><p>for respiratory control, receiving not only tactile information, for example, from the mystacial vibrissae</p><p>(Bosman etal., 2011), but also olfactory input from the nasal mucosa, bypassing the forebrain olfac-</p><p>tory system (Doty etal., 1978; Anton and Peppel, 1991; Schaefer etal., 2002). Stimulation of the</p><p>trigeminal olfactory system can lead to sniffs and respiratory depression without involvement of the</p><p>forebrain (Pérez de Los Cobos Pallares etal., 2016). Activation of the trigeminal olfactory system</p><p>occurs mainly by noxious or irritable gasses, and the resultant respiratory depression is supposed to</p><p>protect the lungs, and may contribute to the diving reflex (Panneton, 2013).</p><p>The anterior ethmoidal nerve, the branchlet of the trigeminal nerve that innervates the nasal</p><p>mucosa, terminates in the interpolar and caudal subnuclei of the spinal trigeminal nucleus (Anton</p><p>and Peppel, 1991; Panneton etal., 2006). From these regions, projections target the pre- Bötzinger</p><p>complex, Kölliker- Fuse nucleus, NTS and lateral parabrachial nucleus (Panneton etal., 2006; Zhang</p><p>etal., 2018), as well as the facial nucleus (Panneton etal., 2006), lateral parafacial nucleus (Bian-</p><p>cardi etal., 2021), cVRG (Li etal., 2021), medial parabrachial nucleus (Hashimoto etal., 2018),</p><p>and periaqueductal gray (Wiberg etal., 1986; Beitz, 1989). In addition, there is direct output to</p><p>the cerebellum (Van Ham and Yeo, 1992; Fu etal., 2011; Henschke and Pakan, 2020) and inferior</p><p>olive (Swenson and Castro, 1983b; Huerta etal., 1985; Molinari etal., 1996; Yatim etal., 1996;</p><p>Panneton etal., 2006). The latter is also indirectly targeted via the MDJ (Kubo etal., 2018).</p><p>Premotor areas</p><p>Although direct projections from central pattern generators and respiratory sensory areas to motor</p><p>neurons do exist, it is likely that indirect pathways via premotor areas are more prominent.</p><p>Retroambiguus nucleus</p><p>The Bötzinger and pre- Bötzinger complexes form a cell column in the ventrolateral medulla that</p><p>continues caudally until the first cervical spinal segment. Caudal to the pre- Bötzinger complex is</p><p>the retroambiguus nucleus that houses inspiratory premotor neurons in its rostral part and expira-</p><p>tory premotor neurons in its caudal part (Merrill, 1970). The respiratory neurons of the retroam-</p><p>biguus nucleus have later been termed the ventral respiratory group. Somewhat confusingly, some</p><p>authors use the terms retroambiguus nucleus and ventral respiratory group as synonyms (Shannon</p><p>and Freeman, 1981), while others refer to the retroambiguus nucleus specifically as the cVRG (Subra-</p><p>manian and Holstege, 2009), or consider the retroambiguus nucleus and cVRG as overlapping areas</p><p>within the caudal medullary reticular formation (Jones etal., 2016). For the purpose of this review,</p><p>we use the terms rVRG for the inspiratory and cVRG for the expiratory part of the ventral respiratory</p><p>column.</p><p>Rostral ventral respiratory group</p><p>The rVRG provides monosynaptic input to the phrenic motor nucleus, and is the most prominent inter-</p><p>mediate between the pre- Bötzinger complex and the diaphragmatic motor neurons (Ellenberger and</p><p>Feldman, 1988; Ellenberger etal., 1990a; Tian and Duffin, 1996; Boulenguez etal., 2007; Buttry</p><p>and Goshgarian, 2015). The direct pathway is complemented by a presumably weaker disynaptic</p><p>pathway via premotor interneurons in the upper cervical (C1 and C2) segments (Lipski etal., 1994;</p><p>Tian and Duffin, 1996; Lane etal., 2008). In addition, the rVRG projects also to the ambiguus, hypo-</p><p>glossal and facial motor nuclei (Yamada etal., 1988; Ellenberger etal., 1990b; Lipski etal., 1994;</p><p>Zheng etal., 1998). The rVRG likely contributes to shaping the pattern of respiratory motor output,</p><p>processing and transmitting sensory afferent information, coordinating ventilation with motor activity,</p><p>and regulating accessory and respiratory muscle activity (Jensen etal., 2019).</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 21 of 67</p><p>The output of the rVRG is not limited to primary motor areas, but targets also the cVRG (Ellen-</p><p>berger and Feldman, 1990; Gerrits and Holstege, 1996) and Kölliker- Fuse nucleus (Ellenberger</p><p>etal., 1990b; Lipski etal., 1994; Yokota etal., 2016), and to a lesser extent also the lateral parafa-</p><p>cial nucleus (Biancardi etal., 2021), reticular formation (Zheng etal., 1998), retrotrapezoid nucleus</p><p>(Rosin etal., 2006), NTS and lateral parabrachial nucleus (Yamada etal., 1988; Ellenberger etal.,</p><p>1990a; Zheng etal., 1998), spinal trigeminal nucleus (Zheng etal., 1998), cerebellum (Gaytán and</p><p>Pásaro, 1998), and inferior olive (Swenson and Castro, 1983a).</p><p>Input to the rVRG does not originate solely in the pre- Bötzinger complex, but comes also from the</p><p>Bötzinger complex (Jiang and Lipski, 1990; Bryant etal., 1993; Ezure etal., 2003), Kölliker- Fuse</p><p>nucleus (Ellenberger and Feldman, 1990; Zheng etal., 1998; Yokota etal., 2016), cVRG (Zheng</p><p>etal., 1998),</p><p>NTS (Ezure and Tanaka, 1996; Zheng etal., 1998), retrotrapezoid nucleus (Rosin etal.,</p><p>2006; Bochorishvili etal., 2012; Silva etal., 2016a), and medial parabrachial nucleus (Yokota etal.,</p><p>2016).</p><p>Caudal ventral respiratory group</p><p>The cVRG is home to expiratory pre- motor neurons (Merrill, 1970; Arita etal., 1987), and therefore</p><p>crucial for the control of expiration- related behavior, like vocalization and expulsive reflexes such as</p><p>vomiting, coughing and sneezing (Umezaki etal., 1997; Subramanian and Holstege, 2009). While</p><p>vocalization depends on the projections to the nucleus ambiguus and spinal cord, expulsive reflexes</p><p>use predominantly the latter only (Holstege, 1989; Umezaki et al., 1997). In particular during</p><p>coughing, the cVRG may trigger also the inspiratory phase (Cinelli etal., 2020).</p><p>Contrary to the rVRG, the cVRG does not project to the phrenic nucleus, but instead innervates</p><p>motor neurons of abdominal muscles in the thoracic spinal cord, and those of the upper airway</p><p>muscles in the ambiguus, hypoglossal, trigeminal, and facial nuclei (Holstege, 1989; VanderHorst</p><p>etal., 2001; Ezure etal., 2003; Boers etal., 2006; Holstege and Subramanian, 2016; Jones etal.,</p><p>2016). Other outputs target pre- Bötzinger and Bötzinger complexes, Kölliker- Fuse nucleus, rVRG,</p><p>retrotrapezoid nucleus, lateral parabrachial nucleus and periaqueductal gray (Holstege, 1989; Gang</p><p>etal., 1995; Zheng etal., 1998; Rosin etal., 2006; Jones etal., 2016). Vocalization- related input</p><p>to the cVRG comes largely from the periaqueductal gray, and this connection is also associated with</p><p>sexual behavior (Holstege, 1989; VanderHorst etal., 2000; Oka etal., 2008; Subramanian and</p><p>Holstege, 2009; Holstege and Subramanian, 2016).</p><p>The cVRG receives both excitatory and inhibitory input from the pre- Bötzinger complex (Gerrits</p><p>and Holstege, 1996; Tan et al., 2010; Yang and Feldman, 2018). Also the Bötzinger complex,</p><p>Kölliker- Fuse nucleus, lateral parafacial nucleus and rVRG project to the cVRG (Fedorko and Merrill,</p><p>1984; Ellenberger and Feldman, 1990; Jiang and Lipski, 1990; Bryant etal., 1993; Gerrits and</p><p>Holstege, 1996; Ezure etal., 2003; Song etal., 2012a; Silva etal., 2016a). Other direct inputs</p><p>come from the NTS (Loewy and Burton, 1978; Beckstead etal., 1980; Gerrits and Holstege, 1996),</p><p>retrotrapezoid nucleus (Gerrits and Holstege, 1996; Rosin etal., 2006; Bochorishvili etal., 2012;</p><p>Silva etal., 2016a), and lateral and medial parabrachial nuclei (Gerrits and Holstege, 1996). A direct</p><p>input from the carotid bodies to the area of the cVRG has been described (Finley and Katz, 1992),</p><p>but this connection did not receive as much attention as that to the NTS.</p><p>Reticular formation</p><p>The hindbrain reticular formation is a highly heterogenous region spanning from the pons to the</p><p>caudal medulla, counting many subdivisions with often unclear borders. While many respiratory</p><p>regions are connected with parts of the reticular formation, this connectivity is difficult to compare</p><p>between different studies, especially considering that the nomenclature of the reticular subdivisions</p><p>has been quite fluid. For this reason, we focus only on those connections with a clear role in respiratory</p><p>control; other connections are summarized in Supplementary file 1. In particular, we mention three</p><p>connections from the pre- Bötzinger complex in which the reticular formation serves as pre- motor</p><p>area. First, there is the connection via the perihypoglossal area to the hypoglossal nucleus that is</p><p>relevant for upper airway control (Chamberlin etal., 2007; Tan etal., 2010; Yang and Feldman,</p><p>2018). Second, two regions serve as premotor areas for the part of the facial nucleus that controls</p><p>among others nose movements: the retrofacial area just caudal to the facial nucleus, and a part of the</p><p>intermediate reticular formation, and both areas probably receive direct input from the pre- Bötzinger</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 22 of 67</p><p>complex (Kurnikova etal., 2019). Third, next to the nose region of the intermediate reticular forma-</p><p>tion is the vibrissal region that links the pre- Bötzinger complex to the vibrissal part of the facial nucleus</p><p>(Moore etal., 2013; Takatoh etal., 2022). The latter two pathways can contribute to the coupling</p><p>of nose movements, whisking and respiration (Welker, 1964; Moore etal., 2013; Kurnikova etal.,</p><p>2019; Romano etal., 2020; Takatoh etal., 2022). The reticular formation could serve a similar pre-</p><p>motor function for the diaphragm as well, as in particular the gigantocellular part projects directly</p><p>to the phrenic nucleus (Ellenberger etal., 1990b; Dobbins and Feldman, 1994; Lois etal., 2009).</p><p>Limbic system</p><p>Of the limbic system, the amygdala and hypothalamus are involved in subconscious control of respira-</p><p>tion. The former is particularly important for handling fear responses, for example, as a consequence</p><p>of high levels of CO2, while the latter is especially important for coupling with the endocrine system, as</p><p>well as for peptidergic modulation of respiration. The lateral hypothalamus is a central chemoreceptor</p><p>area, and – although part of the limbic system – discussed in the section on central chemoreception.</p><p>Central amygdala</p><p>The central amygdala plays a role in CO2- induced fear behavior (Ziemann etal., 2009), and electrical</p><p>stimulation of the central amygdala can indeed affect breathing (Applegate etal., 1983; Harper</p><p>etal., 1984; Nobis etal., 2018). In humans, amygdalar stimulation leads to hypopnea or even apnea</p><p>during nasal breathing, but not during mouth breathing (Nobis et al., 2018), indicating stronger</p><p>impact on the upper airways than on respiratory rhythmogenesis itself.</p><p>Renewed attention for a respiratory role of the central amygdala comes from findings in sudden</p><p>unexpected death in epilepsy (SUDEP). Typically, this sequence leads to SUDEP: rapid breathing after</p><p>a seizure, followed by apnea, bradycardia, and finally cardiac arrest (Ryvlin etal., 2013). Furthermore,</p><p>EEG recordings in patients with epilepsy correlate amygdalar activity with seizure- induced apnea</p><p>(Nobis etal., 2019).</p><p>It has been proposed that the impact of the amygdala on respiratory control is mainly exerted via its</p><p>direct projection to the bed nucleus of the stria terminalis (Nobis etal., 2018). However, as the central</p><p>amygdala gives rise to widespread GABAergic projections, also other connections may be relevant for</p><p>respiratory control (Hopkins and Holstege, 1978; Pape and Pare, 2010; Liu etal., 2021a). Target</p><p>areas include the pre- Bötzinger complex (Yang etal., 2020; Trevizan- Baú etal., 2021a), hypoglossal</p><p>nucleus (Guo etal., 2020), retrotrapezoid nucleus (Rosin etal., 2006), NTS (Gasparini etal., 2020),</p><p>locus coeruleus (Schwarz etal., 2015; Liu etal., 2021a), dorsal raphe (Peyron etal., 1998a; Ogawa</p><p>etal., 2014; Pollak Dorocic etal., 2014; Weissbourd etal., 2014), caudal raphe (Hermann etal.,</p><p>1997), lateral hypothalamus (Yoshida et al., 2006), lateral and medial parabrachial nuclei (Moga</p><p>etal., 1990; Liu etal., 2021a; Yang etal., 2021), periaqueductal gray (Oka etal., 2008; Liu etal.,</p><p>2021a; Trevizan- Baú etal., 2021a), and PPTg (Semba and Fibiger, 1992).</p><p>The central amygdala receives input from the NTS (Kawai, 2018), locus coeruleus (Borodovitsyna</p><p>etal., 2020), dorsal raphe (Bienkowski and Rinaman, 2013), lateral and paraventricular hypothal-</p><p>amus (Fu etal., 2020), bed nucleus of the stria terminalis (Fu etal., 2020), lateral and medial parab-</p><p>rachial nuclei (Bienkowski and Rinaman, 2013), periaqueductal gray (Rizvi etal., 1991), and PPTg</p><p>(Dautan etal., 2016).</p><p>Bed nucleus of the stria terminalis</p><p>The bed nucleus of the stria terminalis is part of the extended amygdala and a main output station of</p><p>the central amygdala (Liu etal., 2021a). It is central to fear, aggression and stress responses (Walker</p><p>etal., 2003; Lebow and Chen, 2016). In relation to respiration, the bed nucleus of the stria terminalis</p><p>may be particularly relevant for anxious responses, or even panic caused by increased levels of CO2</p><p>(Taugher etal., 2014). To this end, the bed nucleus of the stria terminalis expresses relatively high</p><p>levels of acid- sensing ion channel 1A (ASIC1A) (Coryell etal., 2007; Taugher etal., 2014). ASIC1A</p><p>in the bed nucleus of the stria terminalis is also essential for the freezing reaction of mice, which</p><p>implicates a strong reduction in breathing, upon exposure to a predator odor (Taugher etal., 2015).</p><p>Apart from the central amygdala (Dong etal., 2001a; Shin etal., 2008; Lebow and Chen, 2016;</p><p>Ni et al., 2016), other areas targeting the bed nucleus of the stria terminalis are the lateral and</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 23 of 67</p><p>dorsomedial hypothalamus (Shin et al., 2008), NTS (Ricardo and Tongju Koh, 1978; Shin et al.,</p><p>2008; Bienkowski and Rinaman, 2013; Ni etal., 2016; Kawai, 2018), locus coeruleus (Ni etal.,</p><p>2016), dorsal raphe nucleus (Vertes, 1991; Shin etal., 2008; Bienkowski and Rinaman, 2013; Ni</p><p>etal., 2016), lateral parabrachial nucleus (Shin etal., 2008; Bienkowski and Rinaman, 2013; Ni</p><p>etal., 2016; Jaramillo etal., 2021), and periaqueductal gray (Shin etal., 2008; Ni etal., 2016).</p><p>Relating to their functional similarities, the central amygdala and bed nucleus of the stria terminalis</p><p>receive input from the same brain regions, often even from collaterals, except from the substantia</p><p>nigra pars compacta, that does not project to the bed nucleus of the stria terminalis (Bienkowski and</p><p>Rinaman, 2013). This does not imply that all projections are equally strong. In particular, the parabra-</p><p>chial nuclei project stronger to the central amygdala, and the NTS stronger to the bed nucleus of the</p><p>stria terminalis (Bienkowski and Rinaman, 2013).</p><p>Output reaches the central amygdala (Dong etal., 2001b; Fu etal., 2020), lateral, dorsomedial</p><p>and paraventricular hypothalamus (Yoshida etal., 2006; Barbier etal., 2021), NTS (Gasparini etal.,</p><p>2020), locus coeruleus (Luppi etal., 1995; Schwarz etal., 2015), dorsal raphe nuclei (Peyron etal.,</p><p>1998a; Lee etal., 2003; Ogawa etal., 2014; Pollak Dorocic etal., 2014; Weissbourd etal., 2014),</p><p>caudal raphe (Hermann et al., 1997), lateral and medial parabrachial nuclei (Moga et al., 1990;</p><p>Luskin etal., 2021), and PPTg (Steininger etal., 1992).</p><p>Paraventricular hypothalamus</p><p>The paraventricular nucleus of the hypothalamus is vital for the hypoxia reflex: decreased heart rate</p><p>and increased blood pressure and phrenic nerve activity (Kubo etal., 1997; Reddy etal., 2005;</p><p>Ruyle etal., 2019). The paraventricular nucleus is reciprocally connected with the NTS (Rinaman,</p><p>1998; Geerling etal., 2010; King etal., 2012; Gasparini etal., 2020), and the NTS serves both</p><p>as intermediate for the ascending input coming from the carotid bodies, and for the descending</p><p>output affecting the phrenic nucleus (Ruyle etal., 2018; Ruyle etal., 2019). The impact of these</p><p>NTS- projecting paraventricular fibers may be complemented by vasopressinergic connections to the</p><p>phrenic nucleus (Kc etal., 2002), oxytocinergic projections to the pre- Bötzinger complex (Mack etal.,</p><p>2002; Yang etal., 2020; Trevizan- Baú etal., 2021a), or by projections to the Kölliker- Fuse nucleus</p><p>(Yokota etal., 2016; Trevizan- Baú etal., 2021a), PiCo (Oliveira etal., 2021), ambiguus, hypoglossal</p><p>and facial motor nuclei (Mack etal., 2007; Geerling etal., 2010; Guo etal., 2020), reticular forma-</p><p>tion (Geerling etal., 2010), retrotrapezoid nucleus (Rosin etal., 2006; Geerling etal., 2010), locus</p><p>coeruleus (Luppi etal., 1995; Zheng etal., 1995; Schwarz etal., 2015), dorsal and caudal raphe</p><p>(Zheng etal., 1995; Hermann etal., 1997; Peyron etal., 1998a; Lee etal., 2003; Geerling etal.,</p><p>2010; Ogawa etal., 2014; Pollak Dorocic etal., 2014; Weissbourd etal., 2014; Singh etal., 2022),</p><p>lateral hypothalamus (Yoshida etal., 2006; Singh etal., 2022), lateral and medial parabrachial nuclei</p><p>(Zheng etal., 1995; Geerling etal., 2010; Singh etal., 2022), periaqueductal gray (Zheng etal.,</p><p>1995; Geerling etal., 2010; Trevizan- Baú etal., 2021a; Singh etal., 2022), bed nucleus of the stria</p><p>terminalis (Singh etal., 2022), central amygdala (Fu etal., 2020), spinal trigeminal and paratrigem-</p><p>inal nuclei (Zheng etal., 1995; Geerling etal., 2010), PPTg (Zheng etal., 1995; Geerling etal.,</p><p>2010), and cerebellum (Dietrichs, 1984; Çavdar etal., 2018a).</p><p>Apart from the NTS, the lateral and dorsomedial nucleus of the hypothalamus (Thompson etal.,</p><p>1996; Singh et al., 2022), locus coeruleus (Jones and Moore, 1977; Jones and Yang, 1985;</p><p>Cunningham and Sawchenko, 1988), bed nucleus of the stria terminalis (Barbier etal., 2021), and</p><p>lateral parabrachial nucleus (Saper and Loewy, 1980; Fulwiler and Saper, 1984; Moga etal., 1990)</p><p>project to the paraventricular nucleus.</p><p>Dorsomedial hypothalamus</p><p>The dorsomedial hypothalamus is essential for mediating respiratory effects of stressful stimuli (Bond-</p><p>arenko et al., 2015). To this end, it receives input from other hypothalamic regions and the bed</p><p>nucleus of the stria terminalis, as well as from the periaqueductal gray, lateral parabrachial nucleus,</p><p>NTS (Thompson and Swanson, 1998; Do etal., 2020), pre- Bötzinger complex (Yang and Feldman,</p><p>2018), and Kölliker- Fuse nucleus (Geerling etal., 2017).</p><p>The dorsomedial hypothalamus projects predominantly to other hypothalamic nuclei, in particular</p><p>to the paraventricular nucleus, but also to the bed nucleus of the stria terminalis, periaqueductal gray,</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 24 of 67</p><p>NTS (Thompson etal., 1996), Kölliker- Fuse nucleus (Trevizan- Baú etal., 2021a), dorsal and caudal</p><p>raphe (Peyron etal., 2018; Trevizan- Baú etal., 2021a), and cerebellar cortex (Çavdar etal., 2018a).</p><p>Modulatory brain regions</p><p>On top of the central pattern generators, (pre)motor areas, sensory areas and limbic system, also</p><p>other brain regions can affect specific aspects of respiration, often to adapt respiration to other</p><p>behaviors. In fact, few brain regions are completely unrelated to respiration. In the following section,</p><p>we restrict ourselves to those brain regions of which a non- voluntary respiratory function has been</p><p>clearly described.</p><p>Lateral parabrachial nucleus</p><p>The parabrachial nuclei produce a tonic excitatory drive that can, in conjunction with output from the</p><p>Kölliker- Fuse nucleus, contribute to setting the duration of inspiration and expiration (Navarrete-</p><p>Opazo etal., 2020). In addition, the lateral parabrachial nucleus is also crucial in the hypercapnic</p><p>arousal reflex that can trigger waking up during sleep (Kaur etal., 2013). It has been suggested that</p><p>frequent hypercapnic arousals contribute to day- time fatigue and cardiovascular problems in patients</p><p>with obstructive sleep apnea (Abbott and Souza, 2021). The lateral parabrachial nucleus has a tonic</p><p>descending drive and an event- driven ascending one. The latter is consistent with other functions of</p><p>the lateral parabrachial nucleus, as it responds to various aversive signals, varying from food poisoning</p><p>to itch and hypercapnia, and can send a general alarm signal to the forebrain (Palmiter, 2018; Chiang</p><p>etal., 2019; Jaramillo etal., 2021).</p><p>The main outputs target the lateral hypothalamus (Saper and Loewy, 1980; Fulwiler and Saper,</p><p>1984; Moga etal., 1990; Bianchi etal., 1998; Yoshida etal., 2006; Arima etal., 2019), bed nucleus</p><p>of the stria terminalis (Saper and Loewy, 1980; Fulwiler and Saper, 1984; Moga etal., 1990; Bianchi</p><p>etal., 1998; Shin etal., 2008; Bienkowski and Rinaman, 2013; Ni etal., 2016), central amygdala</p><p>(Saper and Loewy, 1980; Moga etal., 1990; Bianchi etal., 1998; Tokita etal., 2010; Bienkowski</p><p>and Rinaman, 2013), and thalamus (Jaramillo etal., 2021). Other targets are the pre- Bötzinger and</p><p>Bötzinger complexes (Gang etal., 1995; Yang etal., 2020; Yu etal., 2022), lateral parafacial nucleus</p><p>(Biancardi et al., 2021), cVRG (Gerrits and Holstege, 1996), ambiguus nucleus (Rübsamen and</p><p>Schweizer, 1986), hypoglossal nucleus (Yokota etal., 2015), retrotrapezoid nucleus (Rosin etal.,</p><p>2006), NTS (Saper and Loewy, 1980; Herbert etal., 1990; Bianchi etal., 1998), locus coeruleus</p><p>(Luppi etal., 1995), dorsal and caudal raphe (Saper and Loewy, 1980; Hermann etal., 1997; Bianchi</p><p>etal., 1998; Lee etal., 2003; Peyron etal., 2018), paraventricular nucleus (Saper and Loewy, 1980;</p><p>Fulwiler and Saper, 1984; Moga et al., 1990; Singh et al., 2022), periaqueductal gray (Bianchi</p><p>etal., 1998), and PPTg (Steininger etal., 1992).</p><p>The main ascending inputs to the lateral parabrachial nucleus come from the spinal cord and NTS</p><p>(Palmiter, 2018). Other inputs come from the pre- Bötzinger and Bötzinger complexes (Tan etal.,</p><p>2010; Yang and Feldman, 2018), Kölliker- Fuse nucleus (Song etal., 2012a; Geerling etal., 2017),</p><p>rVRG (Holstege, 1989), NTS (Beckstead etal., 1980; Herbert etal., 1990; McGovern etal., 2015b;</p><p>Kawai, 2018; Yu etal., 2022), retrotrapezoid nucleus (Rosin etal., 2006; Bochorishvili etal., 2012;</p><p>Silva etal., 2016a), locus coeruleus (Robertson etal., 2013; Yang etal., 2021), dorsal raphe (Petrov</p><p>etal., 1992; Quattrochi etal., 1998; Kaur etal., 2020), bed nucleus of stria terminalis (Moga etal.,</p><p>1990), central amygdala (Moga et al., 1990; Yang et al., 2021), paraventricular nucleus (Zheng</p><p>etal., 1995; Geerling etal., 2010; Singh etal., 2022), spinal trigeminal nucleus (Panneton etal.,</p><p>2006; Zhang etal., 2018), paratrigeminal nucleus (Saxon and Hopkins, 1998; Caous etal., 2001;</p><p>McGovern etal., 2015b; Driessen etal., 2018), PPTg (Quattrochi etal., 1998; Lima etal., 2019b),</p><p>and fastigial nucleus (Teune etal., 2000).</p><p>Medial parabrachial nucleus</p><p>Activity of the medial parabrachial nucleus affects, like that of the lateral parabrachial nucleus, the</p><p>breathing frequency by modulating the duration of expiration (von Euler et al., 1976; Zuperku</p><p>etal., 2017). The medial parabrachial nucleus contains more expiratory neurons than the neighboring</p><p>Kölliker- Fuse nucleus that has more inspiratory and phase- spanning neurons (Song etal., 2006). The</p><p>medial parabrachial nucleus has a dense expression of µ-opioid receptors (Ding etal., 1996) and</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 25 of 67</p><p>plays an important role in the mediation of respiratory depression by opioids (Miller etal., 2017;</p><p>Algera etal., 2019; Saunders and Levitt, 2020). Unlike the lateral parabrachial nucleus, the medial</p><p>parabrachial nucleus is not involved in the hypercapnic arousal reflex (Kaur etal., 2013).</p><p>The medial parabrachial nucleus has both excitatory and inhibitory projections to pre- inspiratory</p><p>neurons in the pre- Bötzinger complex and to expiratory neurons in the Bötzinger complex (Zuperku</p><p>etal., 2019). Activity of the medial parabrachial nucleus can be affected by input from pulmonary</p><p>stretch receptors coming via the NTS (Zuperku et al., 2021), from which it receives direct input</p><p>(Herbert etal., 1990). In addition, it receives input from chemosensitive neurons of the caudal raphe</p><p>nucleus (Brust etal., 2014).</p><p>The medial parabrachial nucleus receives also input from the pre- Bötzinger complex (Tan etal.,</p><p>2010; Yang and Feldman, 2018), Kölliker- Fuse nucleus (Song etal., 2012a; Geerling etal., 2017),</p><p>rVRG (Holstege, 1989), NTS (Loewy and Burton, 1978; Herbert etal., 1990; McGovern etal.,</p><p>2015b), retrotrapezoid nucleus (Rosin etal., 2006), locus coeruleus (Robertson etal., 2013), caudal</p><p>raphe (Brust etal., 2014), bed nucleus of stria terminalis (Moga etal., 1990; Luskin etal., 2021),</p><p>central amygdala (Moga etal., 1990; Liu etal., 2021a; Yang etal., 2021), paraventricular nucleus</p><p>(Zheng etal., 1995; Geerling etal., 2010; Singh etal., 2022), spinal trigeminal nucleus (Hashimoto</p><p>etal., 2018), paratrigeminal nucleus (Saxon and Hopkins, 1998; Caous etal., 2001; McGovern</p><p>etal., 2015b; Driessen etal., 2018), Purkinje cells in the cerebellar cortex (Sugihara etal., 2009;</p><p>Hashimoto etal., 2018), and fastigial nucleus (Teune etal., 2000).</p><p>The medial parabrachial nucleus projects to the pre- Bötzinger and Bötzinger complexes (Gang</p><p>etal., 1995; Yang etal., 2020), lateral parafacial nucleus (Biancardi etal., 2021), rVRG and cVRG</p><p>(Gerrits and Holstege, 1996; Yokota etal., 2016), ambiguus and hypoglossal nuclei (Saper and</p><p>Loewy, 1980; Rübsamen and Schweizer, 1986; Núñez- Abades et al., 1990; Guo et al., 2020),</p><p>retrotrapezoid nucleus (Rosin etal., 2006), NTS (Herbert etal., 1990; Bianchi etal., 1998), locus</p><p>coeruleus (Luppi etal., 1995), dorsal and caudal raphe (Saper and Loewy, 1980; Hermann etal.,</p><p>1997; Bianchi etal., 1998; Lee etal., 2003; Peyron etal., 2018), lateral hypothalamus (Saper and</p><p>Loewy, 1980; Fulwiler and Saper, 1984; Moga etal., 1990; Bianchi etal., 1998), bed nucleus of the</p><p>stria terminalis (Bianchi etal., 1998; Bienkowski and Rinaman, 2013; Ni etal., 2016), central amyg-</p><p>dala (Fulwiler and Saper, 1984; Moga etal., 1990; Bienkowski and Rinaman, 2013), periaqueductal</p><p>gray (Bianchi etal., 1998), and cerebellum (Fu etal., 2011).</p><p>Periaqueductal gray</p><p>The periaqueductal gray, also known as the central gray, contributes to maintaining the homeostatic</p><p>balance of an individual. To this end it participates in controlling defensive, emotional, social, sexual</p><p>and autonomic behaviors, but also in modulating unpleasant sensations, such as pain, itch or the</p><p>urge to cough (Bandler etal., 2000; Linnman etal., 2012; Motta etal., 2017). In addition, the</p><p>periaqueductal gray is central to the control of vocalizations (Magoun etal., 1937; Zhang etal.,</p><p>1994; Esposito etal., 1999; Jürgens, 2002; Subramanian etal., 2021) via its strong projection</p><p>to the cVRG that is the only brain area directly targeting all motor areas required for vocalization</p><p>(VanderHorst etal., 2000; Holstege and Subramanian, 2016). This pathway is especially relevant</p><p>for emotional vocalizations, like crying and laughing, that do not rely on Broca’s area, as human</p><p>speech does (Holstege and Subramanian, 2016). For this reason, the periaqueductal gray can be</p><p>seen as the laughing center, receiving excitatory input from emotion- related pathways originating</p><p>from the basal temporal and frontal lobes, limbic system, and basal ganglia, and inhibition from</p><p>voluntary systems, in particular (pre)motor cortices (Wild etal., 2003; Klingbeil etal., 2021). As to</p><p>the suppression of involuntary laughter, the periaqueductal gray can also contribute to the suppres-</p><p>sion of the urge to cough. The periaqueductal gray sends predominantly GABAergic fibers to the</p><p>NTS (Chen etal., 2022; Figure5F). This can have clinical relevance, as the common condition of</p><p>chronic cough is thought to be caused by hypersensitivity to airway stimulation (Morice et al.,</p><p>2020).</p><p>Although the periaqueductal gray lacks clearly discernible cell groups, specific functions can be</p><p>roughly attributed to four longitudinal columns that differ in their connectivity patterns (Carrive,</p><p>1993). The lateral (lPAG) and dorsolateral (dlPAG) columns are mostly involved in active coping strat-</p><p>egies, such as fight or flight, while the ventrolateral (vlPAG) column is associated with passive coping</p><p>strategies, like freezing (Bandler etal., 2000; Linnman etal., 2012; Faull etal., 2019).</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 26 of 67</p><p>The periaqueductal gray subserves</p><p>several respiratory functions to support stereotypical behavioral</p><p>responses. These functions are distributed over the four cell columns, largely in line with their general</p><p>function (Subramanian etal., 2008; Subramanian, 2013; Faull etal., 2019). Chemical stimulation of</p><p>the dlPAG triggers active breathing, as occurring during fight and flight situations, while stimulation</p><p>of the dorsomedial and the medial part of the lPAG resulted in slow deep breathing and dyspnea, and</p><p>inspiratory apneusis, respectively. Finally, stimulation of the lateral parts of lPAG and vlPAG induced</p><p>respiratory patterns associated with vocalizations (Subramanian etal., 2008).</p><p>The periaqueductal gray is an important hub between the fore- and hindbrain, receiving input</p><p>from multiple cortical areas as well as from the lateral, dorsomedial and paraventricular hypothalamus</p><p>(Beitz, 1989; Zheng etal., 1995; Thompson etal., 1996; Geerling etal., 2010; Trevizan- Baú etal.,</p><p>2021a; Singh etal., 2022). Ascending input to the periaqueductal gray comes directly from the spinal</p><p>cord, and in particular from the upper cervical cord, to the lPAG and vlPAG (Keay etal., 1997). Also</p><p>the NTS, the prime recipient of vagal sensory input, projects to the ventrolateral and medial PAG</p><p>(Herbert and Saper, 1992; Kawai, 2018). Other respiratory centers in the brainstem also project to</p><p>the lPAG and vlPAG: the pre- Bötzinger and Bötzinger complexes, Kölliker- Fuse nucleus (Tan etal.,</p><p>2010; Yang and Feldman, 2018; Trevizan- Baú etal., 2021b), locus coeruleus (Jones and Moore,</p><p>1977; Jones and Yang, 1985), dorsal and caudal raphe (Vertes, 1991; Herbert and Saper, 1992;</p><p>Trevizan- Baú etal., 2021b), lateral and medial parabrachial nuclei (Bianchi etal., 1998), paratrigem-</p><p>inal nucleus (McGovern etal., 2015b), and fastigial and dentate cerebellar nuclei (Teune etal., 2000;</p><p>Frontera etal., 2020).</p><p>Descending output from the periaqueductal gray targets multiple respiratory centers. All four</p><p>columns, but in particular the lPAG and vlPAG, target the pre- Bötzinger complex, Kölliker- Fuse</p><p>nucleus and lateral parafacial nucleus (Tan etal., 2010; Yang and Feldman, 2018; Biancardi etal.,</p><p>2021; Trevizan- Baú etal., 2021b). Ipsilateral connections to the parafacial nucleus are predominantly</p><p>glutamatergic, while contralateral projections have a mixture of glutamatergic and GABAergic fibers</p><p>(Biancardi etal., 2021). The periaqueductal gray innervates also the PiCo (Oliveira etal., 2021),</p><p>retrotrapezoid nucleus (Rosin etal., 2006), NTS (VanderHorst etal., 2000; Chen etal., 2022), locus</p><p>coeruleus (Luppi etal., 1995; Schwarz etal., 2015), dorsal and caudal raphe (Hermann etal., 1997;</p><p>Ogawa etal., 2014; Pollak Dorocic etal., 2014; Peyron etal., 2018; Trevizan- Baú etal., 2021b),</p><p>PPTg (Semba and Fibiger, 1992; Steininger etal., 1992), and inferior olive (Swenson and Castro,</p><p>1983b; VanderHorst etal., 2000). Forebrain projections include the lateral hypothalamus (Woolf</p><p>and Butcher, 1986; Yoshida etal., 2006), bed nucleus of the stria terminalis (Shin etal., 2008; Ni</p><p>etal., 2016), and central amygdala (Rizvi etal., 1991).</p><p>Tegmentum</p><p>The pedunculopontine tegmental nucleus (PPTg) and the adjacent laterodorsal tegmental nucleus</p><p>provide important sources of cholinergic fibers, the activation of which is sufficient to induce REM</p><p>sleep during non- REM sleep (Van Dort etal., 2015). To this end, the pedunculopontine and latero-</p><p>dorsal tegmental nuclei provide widespread innervation of the thalamus and basal ganglia (Mena-</p><p>Segovia and Bolam, 2017), but also of the retrotrapezoid nucleus (Lima etal., 2019b; Silva etal.,</p><p>2019). As the chemoreceptor activity in the retrotrapezoid nucleus can be modulated by acetylcholine</p><p>(Sobrinho etal., 2016), this could imply a different sensitivity to pCO2 during REM sleep. Indeed,</p><p>partial lesioning of the PPTg resulted in abnormal sleep patterns during intermittent hypoxia, while</p><p>leaving basic respiratory parameters intact (Fink etal., 2021).</p><p>Pharmacological activation of muscarinic acetylcholine receptors in the PPTg resulted in decreased</p><p>breathing rates in awake rats (Lima et al., 2019a), and also glutamate injections could suppress</p><p>breathing in anesthetized rats (Saponjic etal., 2003; Topchiy etal., 2010). Inhibition of the PPTg</p><p>resulted in increased inspiratory activity (Silva etal., 2019). Overall, it seems that the PPTg can inhibit</p><p>the function of the retrotrapezoid nucleus, and thereby modulate the respiratory drive. This may be</p><p>particularly relevant during REM sleep, given the interaction between PPTg, hypoxia and disrupted</p><p>sleep patterns (Silva etal., 2019; Fink etal., 2021).</p><p>The target areas of the PPTg are not restricted to those mentioned above, but also include the</p><p>Kölliker- Fuse nucleus (Lima etal., 2019b), lateral parafacial nucleus (Biancardi etal., 2021), hypo-</p><p>glossal, trigeminal and facial motor nuclei (Woolf and Butcher, 1989), locus coeruleus (Woolf and</p><p>Butcher, 1989), dorsal and caudal raphe (Woolf and Butcher, 1989; Hermann etal., 1997; Ogawa</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 27 of 67</p><p>etal., 2014; Lima etal., 2019b), lateral hypothalamus (Woolf and Butcher, 1986), bed nucleus of the</p><p>stria terminalis (Ni etal., 2016), central amygdala (Dautan etal., 2016), lateral parabrachial nucleus</p><p>(Quattrochi etal., 1998; Lima etal., 2019b), spinal trigeminal nucleus (Woolf and Butcher, 1989),</p><p>and all three cerebellar nuclei (Woolf and Butcher, 1989; Ruggiero etal., 1997; Vitale etal., 2016).</p><p>Input to the PPTg comes from the NTS (Steininger etal., 1992), locus coeruleus (Steininger etal.,</p><p>1992), dorsal and caudal raphe (Vertes, 1991; Semba and Fibiger, 1992; Steininger etal., 1992),</p><p>lateral and paraventricular hypothalamus (Semba and Fibiger, 1992; Steininger etal., 1992; Zheng</p><p>etal., 1998; Geerling etal., 2010), bed nucleus of the stria terminalis (Steininger etal., 1992),</p><p>central amygdala (Semba and Fibiger, 1992), lateral parabrachial nucleus (Steininger etal., 1992),</p><p>and cerebellar nuclei (Hazrati and Parent, 1992; Steininger etal., 1992).</p><p>Basal ganglia</p><p>Despite their widespread connectivity and importance for motor control (Roseberry etal., 2016; Lee</p><p>etal., 2020; Quartarone etal., 2020), the basal ganglia are not typically considered to be part of</p><p>the respiratory control network. Possibly the best- known consequence of basal gangliar dysfunction</p><p>is Parkinson’s disease, caused by progressive degeneration of dopaminergic neurons in the substantia</p><p>nigra (Kalia and Lang, 2015). Patients with Parkinson’s disease can be confronted with respiratory</p><p>problems, but these may be attributed to degeneration of respiratory muscles, and therefore not</p><p>directly to respiratory control (Guedes et al., 2012; Baille et al., 2018; Guilherme et al., 2021).</p><p>Patients with Parkinson’s disease may also experience sleep- disturbed breathing or dyspnea (Docu</p><p>Axelerad etal., 2021). With a prevalence of 12%, dyspnea is a relatively rare symptom of Parkinson’s</p><p>disease (Barone etal., 2009), and its cause is unclear (Docu Axelerad etal., 2021). Overall, the basal</p><p>ganglia, and the substantia nigra in particular, therefore, do not seem to play a major role in respira-</p><p>tory control.</p><p>Nevertheless, there are anatomical connections between the substantia nigra and the respiratory</p><p>control centers, including a direct pathway to the pre- Bötzinger complex (Yang etal., 2020). In a</p><p>rat model for Parkinson’s disease, modulation of the retrotrapezoid nucleus by the substantia nigra</p><p>indirectly, via the periaqueductal gray, could contribute to respiratory control (Lima et al., 2018).</p><p>Given the uncertainty of the impact of the basal ganglia on respiratory control, these outputs of the</p><p>substantia nigra have been hypothesized to provide respiratory control centers with information on</p><p>other ongoing movements, to facilitate respiratory</p><p>control into the behavioral context of the animal</p><p>(Yang etal., 2020). For this reason, we did not further consider the basal ganglia as control center for</p><p>the subconscious regulation of respiration.</p><p>Cerebral cortex</p><p>Breathing is rather unique among the autonomic functions as it can be subjected to volitional control,</p><p>modulated by the emotional state, adapted to other ongoing behaviors, and vital for vocalizations</p><p>and human speech. It is quite likely that the cerebral cortex plays an important role in these functions</p><p>(Herrero etal., 2018). Unlike lesions of the subcortical, and in particular of the medullar respiratory</p><p>centers, lesions of cortical respiratory areas do not abolish respiration (Ramirez etal., 2011). The</p><p>anatomical aspects of cortical modulation of respiration have received relatively little attention, and</p><p>we consider the integration of the thalamocortical system into the anatomical scheme of Figure7 an</p><p>important future task.</p><p>There is early evidence for a direct projection from the cat motor cortex to the phrenic nucleus,</p><p>bypassing the medullary respiratory circuitry (Rikard- Bell etal., 1985). In addition, a wide spectrum</p><p>of projections from different cortical areas targets subcortical respiratory control areas, with the most</p><p>numerous projections targeting the periaqueductal gray and the Kölliker- Fuse nucleus, and less abun-</p><p>dant projections to the caudal raphe nucleus, Bötzinger and pre- Bötzinger complexes (Trevizan- Baú</p><p>etal., 2021a). In this study, the Kölliker- Fuse nucleus was predominantly targeted from the (facial)</p><p>somatosensory, endopiriform and rhinal cortices, and the periaqueductal gray from the insular, cingu-</p><p>late, motor, pre- and infralimbic cortices. In addition, the NTS receives a direct projection form the</p><p>insular cortex (Torrealba and Müller, 1996; Gasparini etal., 2020).</p><p>In the context of the present review, especially the function of the insular cortex is relevant. It</p><p>appears to be the prime cortical target area of visceral input, and it has a viscerotopic organization</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 28 of 67</p><p>Inspiration Post-in</p><p>sp</p><p>ira</p><p>tio</p><p>n</p><p>Active expiration</p><p>Inferior</p><p>olive</p><p>Cerebellar</p><p>nuclei</p><p>Jaw</p><p>Carotid bodies</p><p>Upper airways</p><p>Heart</p><p>Nose</p><p>Lower airways</p><p>Abdomen</p><p>O2 CO2</p><p>Phrenic</p><p>nucleus</p><p>Thoracic</p><p>spinal</p><p>cord</p><p>Trigeminal</p><p>motor</p><p>nucleus</p><p>Facial</p><p>nucleus</p><p>Hypo-</p><p>glossal</p><p>nucleus</p><p>Cervical</p><p>spinal</p><p>cord</p><p>Ambiguus</p><p>nucleus</p><p>Semi-circular canals</p><p>Vibrissae</p><p>Tongue</p><p>Intercostal muscles</p><p>Diaphragm</p><p>Dorso-</p><p>medial</p><p>hypothal.</p><p>Paraventri-</p><p>cular</p><p>hypothal.</p><p>NTS</p><p>Central</p><p>amygdala</p><p>BNST</p><p>Retro-</p><p>trapezoid</p><p>nucleus</p><p>CO2</p><p>Locus</p><p>coeruleus</p><p>Dorsal</p><p>raphe</p><p>CO2</p><p>Caudal</p><p>raphe</p><p>CO2</p><p>Lateral</p><p>hypo-</p><p>thalamus</p><p>CO2</p><p>Clarke’s</p><p>column</p><p>PiCo</p><p>Lateral</p><p>parafacial</p><p>nucleus</p><p>Bötzinger</p><p>complex</p><p>Periaque-</p><p>ductal</p><p>gray</p><p>PPTg</p><p>LPBN</p><p>MPBN</p><p>Reticular</p><p>formation cVRGrVRG</p><p>Cerebellar</p><p>cortex</p><p>Vestibular</p><p>nuclei</p><p>Basal</p><p>ponsMDJ</p><p>Pre-</p><p>Bötzinger</p><p>complex</p><p>CO2</p><p>Para-</p><p>trigeminal</p><p>nucleus</p><p>Spinal</p><p>trigeminal</p><p>nucleus</p><p>CO2</p><p>CO2</p><p>Kölliker-</p><p>Fuse</p><p>nucleus</p><p>Figure 7. Main pathways underlying subconscious control of respiration Schematic drawing representing the brain areas most involved in subconscious</p><p>control of respiration and the main pathways connecting them. Fat lines indicate relatively strong connections and thin lines moderately strong ones.</p><p>Sparse connections are not included in this scheme. When an area is marked with ‘CO2’ it contains central chemoreceptor properties, while the carotid</p><p>bodies sense blood levels of CO2 and of O2. The central pattern generators are indicated with a sine wave. BNST = bed nucleus of the stria terminalis;</p><p>Figure 7 continued on next page</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 29 of 67</p><p>(Cechetto and Saper, 1987; Bagaev and Aleksandrov, 2006; Livneh and Andermann, 2021). EEG</p><p>recordings of the insular cortex revealed coherence with breathing (Herrero etal., 2018). Depending</p><p>on the location within the insular cortex, microstimulation could either increase or decrease the respi-</p><p>ratory rate (Bagaev and Aleksandrov, 2006), suggesting that the insular cortex can affect respiration</p><p>in response to vagal sensory input.</p><p>Cerebellum</p><p>The cerebellum is composed of a cortex surrounding the fastigial, interposed and dentate nuclei.</p><p>The output of the cerebellar cortex is formed by Purkinje cells that predominantly target the cere-</p><p>bellar nuclei (Voogd and Glickstein, 1998), although direct connections to the vestibular nuclei, locus</p><p>coeruleus, and lateral and medial parabrachial nuclei exist as well (Zeeuw and Berrebi, 1995; Sada-</p><p>kane etal., 2000; Sugihara etal., 2009; Schwarz etal., 2015; Hashimoto etal., 2018; Novello</p><p>etal., 2022). From the cerebellar nuclei, there are projections back to the cerebellar cortex (Tolbert</p><p>etal., 1977; Gao etal., 2016), inhibitory projections to the inferior olive (Voogd and Glickstein,</p><p>1998), and excitatory projections to the MDJ (De Zeeuw and Ruigrok, 1994; Wang etal., 2022) and</p><p>many brain regions relevant for respiratory control.</p><p>Strikingly, there are no direct connections to the phrenic nucleus (Lois etal., 2009), nor to the</p><p>pre- Bötzinger complex (Yang etal., 2020). Instead, diaphragmatic activity can be affected by a direct</p><p>projection to the premotor rVRG (Gaytán and Pásaro, 1998). Although there are direct projections</p><p>from the cerebellum to the trigeminal motor nucleus, affecting upper airway muscles (Judd etal.,</p><p>2021), facial nucleus (Moolenaar and Rucker, 1976; Fujita etal., 2020), and hypoglossal nucleus</p><p>(Guo etal., 2020; Judd etal., 2021), these direct projections to motor nuclei are typically relatively</p><p>sparse so that indirect projections, for example, via the reticular formation, are probably much more</p><p>abundant (Novello etal., 2022).</p><p>Other cerebellar projections that can be relevant for respiratory control target the Kölliker- Fuse</p><p>nucleus (Fujita etal., 2020), locus coeruleus (Teune etal., 2000; Schwarz etal., 2015), dorsal raphe</p><p>nuclei (Teune etal., 2000; Çavdar etal., 2018b), periaqueductal gray (Teune etal., 2000; Frontera</p><p>etal., 2020; Fujita etal., 2020; Judd etal., 2021), lateral and paraventricular hypothalamus (Diet-</p><p>richs etal., 1994; Zhu etal., 2006). Many of these areas, in particular the Kölliker- Fuse nucleus, have</p><p>profound projections to medullary respiratory circuit, so that these projections can explain how the</p><p>cerebellum can affect respiratory control.</p><p>Despite the absence of strong pathways from the cerebellum to the respiratory pattern generators</p><p>and motor nuclei, cerebellar activity can profoundly modulate respiration. Functional brain imaging</p><p>of healthy human subjects revealed that the cerebellum is particularly active during coping with respi-</p><p>ratory challenges: broad activation during hypoxia and slow breathing (Critchley etal., 2015), and</p><p>specific activation in lobules V and VI during hypercapnia (Colebatch etal., 1991; Kastrup etal.,</p><p>1999). Also the cerebellar nuclei are active during hypercapnia and hypoxia (McKay etal., 2010), as</p><p>well as during volitional expiration (Ramsay etal., 1993). Changes in environmental air pressure can</p><p>trigger cerebellar activity as well (Isaev etal., 2002; Raux etal., 2013; Figure6G–J).</p><p>The notion that the cerebellum is particularly relevant for deviating from rhythmic breathing is</p><p>corroborated by the finding that mice suffering from a complete lack of output from the cerebellar</p><p>cortex or from a partial loss of cerebellar output neurons display overly regular breathing at rest (Liu</p><p>etal., 2020; Taylor etal., 2022; Figure6F). Stimulation of the fastigial nucleus in cats can affect</p><p>phrenic nerve activity, and in particular terminate expiratory activity when stimulated during expiration</p><p>(Zhang etal., 1999), analogous to optogenetic stimulation experiments</p><p>of Purkinje cells (Romano</p><p>etal., 2020; Figure6E). And indeed, Lurcher mice that suffer from a complete loss of Purkinje cells</p><p>during their development, demonstrated impaired responses to hypercapnic and hypoxic challenges</p><p>(Calton etal., 2014; Calton etal., 2016). Neuronal activity of the cerebellar cortex and the fastigial</p><p>nucleus is linked to respiration (Lutherer etal., 1989; Gruart and Delgado- García, 1992; Cao etal.,</p><p>2012b; Lu et al., 2013; Romano et al., 2020; Figure 6C–D). At rest, modulation of the activity</p><p>cVRG = caudal ventral respiratory group; LPBN = lateral parabrachial nucleus; MPBN = medial parabrachial nucleus; NTS = nucleus tractus solitarii; PiCo</p><p>= postinspiratory complex; PPTg = peripeduncular tegmental nucleus; rVRG = rostral ventral respiratory group. See also Supplementary file 1.</p><p>Figure 7 continued</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 30 of 67</p><p>of Purkinje cell occurs without phase lead or lag relative to the respiratory cycle (Romano et al.,</p><p>2020), and one could speculate that the cerebellum does not only act to adapt respiration to ongoing</p><p>behavior, but also facilitates adaptation of other behavior to respiration, in line with observations in</p><p>cerebellar patients (Ebert etal., 1995).</p><p>The cerebellum may, in addition, have a particular role in the regulation of breathing during sleep,</p><p>which includes different stages with different respiratory and oculomotor dynamics (Canto et al.,</p><p>2017; De Zeeuw and Canto, 2022; Pujol etal., 2022). Indeed, when shifting from awake to subcon-</p><p>scious behavior and vice- versa, different brain structures such as cerebellum, hippocampus and amyg-</p><p>dala, are dynamically activated and de- activated in line with changes in breathing (Pujol etal., 2022).</p><p>Accordingly, the impact of sleep on breathing and its role in the development of diurnal respiratory</p><p>failure in patients suffering from hypoventilation and/or cerebellar disorders can be overlooked (Piper</p><p>and Yee, 2014; Canto etal., 2017). It remains to be elucidated which sets of mechanisms are involved</p><p>in this process, but it should be noted that sleep by itself does not only reduce respiratory drive, but</p><p>also diminishes responsiveness to hypoxia and hypercapnia. For example, acute increases in CO2</p><p>during rapid eye movement sleep can initiate the process of bicarbonate retention, which further</p><p>depresses ventilatory responsiveness (Piper and Yee, 2014) and which in turn can affect activity in the</p><p>cerebellar nuclei (Parsons etal., 2001; Martino etal., 2007).</p><p>Mossy fiber inputs</p><p>Mossy fibers constitute one of the two main glutamatergic input pathways to the cerebellum. They</p><p>carry ascending as well as descending information to granule cells in the cerebellar cortex, while often</p><p>forming collaterals to the cerebellar nuclei (van der Want etal., 1987; Huang etal., 2013; Ruigrok</p><p>etal., 2015). Cerebellar granule cells make up about halve of all neurons in the brain, and their bifur-</p><p>cating axons, the parallel fibers, target Purkinje cells directly, and indirectly via inhibitory interneurons</p><p>(Harvey and Napper, 1991; De Zeeuw etal., 2011; Ruigrok etal., 2015).</p><p>The pontine nuclei, consisting of the basal pons and the nucleus reticularis tegmenti pontis, are the</p><p>prime source of mossy fibers; not only are they the main intermediate for descending pathways from</p><p>the cerebral cortex, they also receive subcortical input from among others the lateral hypothalamus,</p><p>central amygdala, periaqueductal gray, spinal trigeminal nucleus, PPTg, MDJ, and cerebellar nuclei</p><p>(Mihailoff etal., 1989; Brodal and Bjaalie, 1992; Liu and Mihailoff, 1999; Pijpers and Ruigrok,</p><p>2006; Bosman etal., 2011; Fu etal., 2011; Huang etal., 2013; Ruigrok etal., 2015; Henschke and</p><p>Pakan, 2020).</p><p>Other important mossy fiber sources are the two vagal sensory nuclei relating respiratory visceral</p><p>input to the brain, the NTS (Batini etal., 1978; Somana and Walberg, 1979a; Saigal etal., 1980a;</p><p>Fu et al., 2011) and paratrigeminal nucleus (Somana and Walberg, 1979b). Strong mossy fiber</p><p>connections bind also the spinal trigeminal nucleus, medial parabrachial nucleus, and several parts</p><p>of the medullary reticular formation with the cerebellum (Ruigrok etal., 1995; Yatim etal., 1996;</p><p>Fu etal., 2011). This is also true for multiple spinal regions (Sengul etal., 2015; Baek etal., 2019).</p><p>Weaker projections come from the lateral parabrachial nucleus (Fu etal., 2011), Kölliker- Fuse nucleus</p><p>(Fu etal., 2011), and rVRG (Gaytán and Pásaro, 1998). The pre- Bötzinger complex provides only</p><p>sparse projections to the cerebellum (Yang and Feldman, 2018).</p><p>Climbing fiber inputs</p><p>The other main input to the cerebellum is formed by the climbing fibers that originate exclusively from</p><p>the contralateral inferior olive and that form extraordinarily strong glutamatergic synapses on Purkinje</p><p>cells, next to relatively weak collateral projections to the cerebellar nuclei (Szentágothai and Rajko-</p><p>vits, 1959; Ruigrok etal., 2015; Lu etal., 2016). Where each adult Purkinje cell can receive input</p><p>from over 100,000 parallel fibers, it is typically innervated by only a single climbing fiber (Harvey and</p><p>Napper, 1991; Bosman and Konnerth, 2009). Climbing fiber spikes invariably trigger complex spike</p><p>firing by the postsynaptic Purkinje cells, and these consist of normal action potentials in conjunction</p><p>with dendritic spikelets caused by profound influx of calcium (Llinás and Sugimori, 1980; De Zeeuw</p><p>etal., 2011). Because of their impact on intracellular calcium levels, complex spikes affect the synaptic</p><p>strength of parallel fiber inputs, and thereby control cerebellar learning (Ito, 2000; Coesmans etal.,</p><p>2004; Ohtsuki etal., 2009; van Woerden etal., 2009; Gao etal., 2012; Yang and Lisberger, 2014;</p><p>Romano etal., 2018). Accordingly, climbing fiber activity is strictly regulated, occurs at a sustained,</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 31 of 67</p><p>but low rate, and can thereby serve a homeostatic function at rest, while reporting salient events when</p><p>they occur (Zhou etal., 2014; Ju etal., 2019; Negrello etal., 2019; Bina etal., 2021). In general, the</p><p>complex spikes therefore modulate the activity pattern of simple spikes, that organize motor output.</p><p>Apart from the cerebellum, the most important input areas to the inferior olive are the spinal</p><p>cord (Brown etal., 1977), periaqueductal gray (Brown etal., 1977; Swenson and Castro, 1983b;</p><p>VanderHorst etal., 2000), spinal trigeminal nucleus (Swenson and Castro, 1983b; Huerta etal.,</p><p>1985; Van Ham and Yeo, 1992; Yatim etal., 1996), and MDJ (de Zeeuw etal., 1989; Wang etal.,</p><p>2022). The MDJ is the main intermediate between the cerebral cortex and the inferior olive: it relays</p><p>input from the rostromedial and caudal parts of the cerebral cortex to the principal olive, and from</p><p>the rostrolateral parts of the cerebral cortex to the medial accessory olive (Wang etal., 2022). In</p><p>addition, the MDJ receives input from the spinal trigeminal nucleus (Kubo etal., 2018) and the cere-</p><p>bellar nuclei (De Zeeuw and Ruigrok, 1994; Wang etal., 2022). Input to the inferior olive comes</p><p>also from the two vagal sensory recipient nuclei: NTS (Loewy and Burton, 1978; McGovern etal.,</p><p>2015b) and paratrigeminal nucleus (McGovern etal., 2015b), as well as from rVRG (Swenson and</p><p>Castro, 1983b).</p><p>Other cerebellar inputs</p><p>Other cerebellar afferents could potentially contribute to respiratory control, although their precise</p><p>impact has not yet been studied. Hypothalamocerebellar connections are evolutionary preserved, but</p><p>more prominent in primates than in rodents (Dietrichs, 1984; Dietrichs etal., 1994). They originate</p><p>from several hypothalamic nuclei. In the context of this review, orexinergic fibers from the lateral</p><p>hypothalamus to</p><p>the cerebellar nuclei seem to be the most relevant, possibly in conjunction with a</p><p>projection from the paraventricular nucleus (Dietrichs, 1984; Haines etal., 1997; Zhu etal., 2006;</p><p>Yu etal., 2010; Çavdar etal., 2018a).</p><p>The locus coeruleus provides widespread noradrenergic innervation of the cerebellar cortex and</p><p>nuclei (Olson and Fuxe, 1971; Saigal etal., 1980a; Loughlin etal., 1986; Dietrichs, 1988; Szabadi,</p><p>2013), which could contribute to a general modulation of cerebellar output (Parfitt etal., 1988; Di</p><p>Mauro etal., 2013; Lippiello etal., 2015). Also both the dorsal and caudal raphe nuclei project to</p><p>the cerebellar cortex and nuclei, providing serotonergic input (Shinnar etal., 1975; Pierce etal.,</p><p>1977; Bishop and Ho, 1985; Fu etal., 2011), which can have profound impact on cerebellar function</p><p>(Kawashima, 2018). In mild forms of cerebellar ataxia, application of a serotonin receptor agonist</p><p>could alleviate various motor symptoms (Takei etal., 2005). These, and the other anatomical projec-</p><p>tions, are summarized in Figure7.</p><p>Cerebellar pathology</p><p>Although the role of the cerebellum in respiratory control is not yet settled in clinical settings, several</p><p>lines of evidence indicate a specific role in respiratory control. For instance, in some developmental</p><p>disorders, cerebellar abnormalities and respiratory dysfunction co- occur. Arguably, the most explicit</p><p>example is sudden infant death syndrome (SIDS), the unexplained abrupt death of infants, typically</p><p>during sleep, and most likely related to respiratory problems (Kelly etal., 1986; Kinney and Thach,</p><p>2009). Several studies link SIDS to cerebellar malformations. For instance, post- mortem analyses</p><p>relate SIDS to the presence of a wide external granular layer, which is a sign of developmental delay</p><p>of the cerebellum (Cruz- Sánchez etal., 1997; Lavezzi etal., 2007a). Also malformed and displaced</p><p>Purkinje cells were observed in several cases (Lavezzi etal., 2013; Matschke etal., 2020). Addition-</p><p>ally, the dentate- olivary system can be affected in SIDS (Lavezzi etal., 2007b). Note that malforma-</p><p>tions of the cerebellum and related structures have been demonstrated only in a subset of cases, as</p><p>SIDS can have multiple causes (Kinney and Thach, 2009; Figure8B).</p><p>Nevertheless, respiratory deficiencies and prolonged dependency on assisted or even mechanical</p><p>ventilation are frequently observed after cerebellar damage (Chen etal., 2005; Tsitsopoulos etal.,</p><p>2012; Lee etal., 2013; Arnone etal., 2017). Relatively mild aberrations in respiratory functions were</p><p>also noted in different types of spinocerebellar ataxia (Sriranjini etal., 2010), while in a mouse model</p><p>for spinocerebellar ataxia type 7 (SCA7) abnormal respiratory patterns were recorded (Figure8B–C).</p><p>Distinct types of spinocerebellar ataxia can affect various brain regions relevant for subconscious</p><p>control of respiration (Figure8B, Supplementary file 1). Finally, chronic cough may be one of the</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 32 of 67</p><p>B</p><p>C D</p><p>SCA2</p><p>SCA7</p><p>LV</p><p>Mo5</p><p>BPn</p><p>RF</p><p>TMN</p><p>Ck</p><p>SpV</p><p>Cx</p><p>IO</p><p>IO</p><p>Vest</p><p>7N NA</p><p>SCA3 SCA6</p><p>SCA7 CANVAS SIDS</p><p>LC</p><p>NTS</p><p>12N</p><p>LV</p><p>Mo5</p><p>BPn</p><p>RF Ck</p><p>SpV</p><p>Cx</p><p>CN</p><p>IO</p><p>Vest</p><p>7N NA</p><p>12N</p><p>CSC</p><p>LV</p><p>Cx</p><p>CN</p><p>LV</p><p>Cx</p><p>CN</p><p>CR</p><p>LV</p><p>Cx</p><p>LV</p><p>Cx</p><p>Affected</p><p>Not affected</p><p>CN</p><p>CN</p><p>BPn</p><p>12N</p><p>A Normal respiration</p><p>1</p><p>1 Cheyne-Stokes respiration</p><p>30 s</p><p>1 min</p><p>30 s</p><p>30 s</p><p>30 s</p><p>30 s</p><p>30 s</p><p>30 s</p><p>1 s 10 s</p><p>1</p><p>2</p><p>Apneusis2</p><p>3</p><p>Obstructive sleep apnea3</p><p>4</p><p>Biot’s respiration4</p><p>5</p><p>Respiratory arrest5</p><p>7</p><p>COPD7</p><p>6</p><p>Abnormal rhythmicity of respiration6</p><p>Stim</p><p>Figure 8. Pathology. (A) Based on the location of a lesion or structural abnormality, several types of disordered breathing can be expected. Cheyne-</p><p>Stokes respiration can result from a bilateral hemispheric or diencephalic lesion. Apneustic breathing has originally been described as the consequence</p><p>of a lesion at the level of the Kölliker- Fuse nucleus, but can probably also be caused by damage to surrounding tissue. A Biot’s respiration pattern can</p><p>develop after a lesion in the medulla, while a respiratory arrest occurs after damage to the pre- Bötzinger complex or the upper spinal cord. Obstructive</p><p>Figure 8 continued on next page</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 33 of 67</p><p>earliest symptoms of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS),</p><p>and manifests in the absence of any perceived lung abnormalities (Infante etal., 2018).</p><p>Disordered breathing</p><p>Lesions, e.g., as a consequence of hemorrhage, at different levels of the brain can result in different</p><p>patterns of disordered breathing (Figure8A).</p><p>A bilateral hemispheric or diencephalic lesion can lead to Cheyne- Stokes respiration (Brown and</p><p>Plum, 1961). This is characterized by an undulating pattern of breathing with increasing depth and</p><p>frequency alternated with waves of shallow, slower breathing (Lorenzi- Filho etal., 1999).</p><p>Apneustic breathing, characterized by the absence or extreme delay of the inspiration to expira-</p><p>tion switch, has originally been described as the consequence of a lesion at the level of the Kölliker-</p><p>Fuse nucleus or the surrounding area (Marckwald, 1890; Lumsden, 1923; Caille etal., 1981; Mador</p><p>and Tobin, 1990).</p><p>Biot’s respiration is characterized by irregular periods of apnea alternated by several breaths of</p><p>identical depth (Farney et al., 2003; Wijdicks, 2007). Although, the irregularity of this breathing</p><p>pattern has led to the more common term ‘ataxic breathing’, the cerebellum is not primarily involved</p><p>in this type of respiration (Summ etal., 2022). However, Biot’s respiration pattern can result after a</p><p>lesion in the medulla (Summ etal., 2022). Biot’s respiration can also be a complication of long- term</p><p>opioid use (Farney etal., 2003).</p><p>Finally, a respiratory arrest can result after damage to the pre- Bötzinger complex or the upper</p><p>spinal cord (Ramirez etal., 1998; Schwarzacher etal., 2011; Arora etal., 2012).</p><p>Animal experiments have demonstrated that a lack of cerebellar output can lead to hyperregular</p><p>respiration (Liu etal., 2020; Taylor etal., 2022). Cerebellar patients, however, can also display the</p><p>opposite and present with irregular respiration (Ebert etal., 1995). Both, hyperregular as well as</p><p>irregular breathing, can be the consequence of impaired coordination of respiration with ongoing</p><p>behavior, as described for instance by Ebert etal., 1995.</p><p>While each of these brain areas result in a specific type of respiratory pattern. It must be noted</p><p>that a specific respiratory pattern can have multiple causes such as metabolic or cardiopulmonary</p><p>disorders. In addition, also peripheral diseases, like COPD (Jolley etal., 2009), can cause disordered</p><p>breathing. COPD is a chronic obstructive pulmonary condition characterized by abnormalities, espe-</p><p>cially narrowing of the small airways, of the lung which leads to limitation of the airflow.</p><p>Coordination of different behaviors</p><p>Throughout this review, we have discussed several behaviors that are tightly coupled to respiration,</p><p>such as those involved in airway clearance, feeding, and vocalization, as well as adjusting the rate of</p><p>ventilation to metabolic demands. In addition, also postural control and cardiovascular function are</p><p>linked to respiration. All pump muscles have dual functions; they do not only enable ventilation but</p><p>control also posture and movements (Ebert etal., 2000). The coordination between these different</p><p>tasks can be affected in cerebellar patients, displaying regular breathing at rest, but arhythmic</p><p>breathing during arm movements (Ebert etal., 1995).</p><p>sleep apnea typically shows interrupted breathing pattern during sleep. Cerebellar dysfunction can lead to more (left) or less (right) rhythmic respiration.</p><p>COPD patients show increased respiratory</p><p>rates and reduced passive expiration. It should be noted however that cardiopulmonary or metabolic causes</p><p>can also trigger all these respiratory patterns. Schematized traces of the tidal volume based on: Cheyne- Stokes respiration: Lorenzi- Filho etal., 1999;</p><p>Apneusis: Mador and Tobin, 1990; Biot’s respiration: Farney etal., 2003: Abnormal rhythmicity: Ebert etal., 1995; COPD (and normal): Jolley etal.,</p><p>2009. (B) Respiration- related brain areas demonstrating structural damage in several disorders, projected in the same notation as in Figure2A. Note</p><p>that SCA6 is mainly a cerebellar disorder. While CANVAS affects the cerebellum, the syndrome has also peripheral nerve involvement. In SIDS multiple</p><p>non- cerebellar causes have been described in post mortem studies. Some post mortem brain studies, however, have shown irregularly formed Purkinje</p><p>cells in the cerebellar cortex. See Supplementary file 1. (C) Apneustic breathing pattern in a mouse model of spinocerebellar ataxia type 7. Schematic</p><p>representation based on Fusco etal., 2021. (D) Electrical stimulation (Stim) adjacent to the fastigial nucleus induces a fastigial pressor response in an</p><p>anesthetized cat. During stimulation, the tidal volume is increased, and suppressed afterwards. Based on Miura and Takayama, 1988.</p><p>Figure 8 continued</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 34 of 67</p><p>Brain rhythms</p><p>Global and local rhythms abound in the brain, and they have been proposed to arrange long- range</p><p>synchrony and functional coupling, and thus play a vital role in motor control, sensory perception,</p><p>and conscious processing (Llinás, 1988; Khoshyomn etal., 1999; Mantini etal., 2007; Fries, 2015;</p><p>Lindeman etal., 2021). There is accumulating evidence that the respiratory rhythm can affect these</p><p>brain rhythms.</p><p>In the olfactory system, a coupling between respiration and rhythmic activity was noticed already a</p><p>long time ago (Adrian, 1942; Fontanini etal., 2003). As odorants are carried by air, each sniff brings</p><p>in new information, and can be considered as the temporal unit of olfaction (Kepecs etal., 2006;</p><p>Verhagen etal., 2007). Sniffing can, however, be more widely seen as patterning sensory processing,</p><p>as it, for instance, can dynamically synchronize with whisking (Welker, 1964; Cao etal., 2012a; Moore</p><p>etal., 2013). A hint that respiration is even more related to brain function comes from the observation</p><p>that humans tend to inhale at the start of a cognitive test, even if that does not involve olfaction (Perl</p><p>etal., 2019). This goes so far that a change in performance on a visuospatial task varies between</p><p>inspiration and expiration was observed in line with alteration in the EEG spectrum (Perl etal., 2019).</p><p>In fact, respiration- induced patterns in neural oscillations are ubiquitously observed throughout the</p><p>brain (Ito etal., 2014; Yanovsky etal., 2014; Heck etal., 2016; Zelano etal., 2016; Tort etal.,</p><p>2018; Kluger and Gross, 2021).</p><p>Changes in brain oscillations are by no means restricted to the frequency domain of respiration or</p><p>sniffing. Gamma oscillations (30–100Hz), which could reflect sensorimotor integration (Zagha etal.,</p><p>2013; Lindeman etal., 2021), can show changes in power that are phase- locked to the respiratory</p><p>rhythm (Ito etal., 2014; Kluger and Gross, 2021). Respiration can, therefore, serve as a scaffold for</p><p>sensory, sensorimotor and cognitive functions.</p><p>Cardiorespiratory function</p><p>Ventilation is only one aspect of the ultimate goal of respiration: getting oxygen to mitochondria</p><p>throughout the body, while maintaining balanced concentrations of O2 and CO2 in the blood. Hence,</p><p>respiration has to be coordinated with cardiac and vascular regulation, a process collectively known as</p><p>cardiorespiratory function. Ineffective cardiorespiratory function is an important predictor for devel-</p><p>opment of averse cardiovascular events and mortality, and has a higher predictive value than for</p><p>example, smoking or hypertension (Lee etal., 2010; Ross etal., 2016).</p><p>An example of the integrated control of cardiovascular and respiratory function is the fastigial</p><p>pressor response that entails simultaneous increases in heart rate and arterial pressure with changes</p><p>in ventilation (Miura and Reis, 1969; Achari and Downman, 1970; Lutherer and Williams, 1986;</p><p>Bradley etal., 1987; Xu and Frazier, 2000; Hernandez etal., 2004; Nisimaru, 2004). The specificity</p><p>of the fastigial nucleus for triggering the fastigial pressor response has been called into question,</p><p>arguing that it was actually caused by activation of the passing afferents to the lateral parabrachial</p><p>nucleus (Miura and Takayama, 1988). Yet, lesioning of the fastigial nuclei does lead to impairment of</p><p>the fastigial pressor response (Zhuang etal., 2008; Figure8D).</p><p>Cardiac and respiratory regulation are coupled on a cycle- by- cycle basis, as the heart rate</p><p>increases during inspiration, and decreases again during post- inspiration and active expira-</p><p>tion (Hirsch and Bishop, 1981; Elstad et al., 2018). Respiratory sinus arrhythmia is caused by</p><p>respiration- related fluctuations in activity of inhibitory preganglionic parasympathetic cardiac vagal</p><p>neurons that are primarily located in the nucleus ambiguus (McAllen and Spyer, 1976; Neff etal.,</p><p>2003; Dergacheva etal., 2010). The Kölliker- Fuse nucleus provides the phasic excitatory drive</p><p>to these cardiac premotor neurons that is required for respiratory sinus arrhythmia (Farmer etal.,</p><p>2016).</p><p>Stimulation of pro- opiomelanocortin- producing neurons in the NTS can augment respiratory sinus</p><p>arrhythmia, along with triggering suppressed breathing (bradypnea) and cardiac function (brady-</p><p>cardia) (Cerritelli etal., 2016). Pro- opiomelanocortin is a precursor of the opioid ß-endorphin, and</p><p>its impact of cardiovascular function can be mimicked by administered opioids (Walker etal., 2007;</p><p>Izrailtyan etal., 2018). The pro- opiomelanocortin neurons of the NTS directly target important respi-</p><p>ratory centers as the pre- Bötzinger complex, giving rise to bradypnea, the ambiguus nucleus, giving</p><p>rise to bradycardia, and the hypoglossal nucleus, rVRG, hypoglossal nucleus, and raphe obscurus</p><p>nucleus (Cerritelli etal., 2016; Figure5E).</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 35 of 67</p><p>Ideas and speculations</p><p>It is an attractive idea to have one or a few central pattern generator areas that control the respiratory</p><p>rhythm (Moore etal., 2013; Anderson and Ramirez, 2017). In particular, the pre- Bötzinger complex</p><p>is essential in this respect, as inspiration depends on it (Smith etal., 1991; Ramirez etal., 1998; Gray</p><p>etal., 2001; Tan etal., 2008; Schwarzacher etal., 2011; Ashhad and Feldman, 2020; Dhingra</p><p>etal., 2020). In this view, projections organized in a hierarchical fashion pass the respiratory control</p><p>from the pattern generator(s) to the respiratory motor neurons. Throughout this review we summarize,</p><p>however, that many other brain regions, including areas like the cerebellum and the limbic system</p><p>that are not classically considered to be respiratory areas, can affect respiratory control (Figure8).</p><p>As all these areas are interconnected (Figure7), the picture of an integrated network emerges. Thus,</p><p>depending on specific behavioral needs, these other brain regions may modulate or even overrule the</p><p>central pattern generators. This does not contradict the idea of central pattern generators being the</p><p>main players that control rhythmic respiration, but postulates that these pattern generators together</p><p>with their downstream areas are themselves embedded in a larger network that allows for flexibility</p><p>within the respiratory control system. We therefore suggest to view the respiratory control system</p><p>primarily as an integrated network, rather than a hierarchical system.</p><p>differ in strength or in their ratio between excitatory and inhibitory fibers, potentially introducing</p><p>asymmetries in motor activity (Biancardi etal., 2021). As detailed studies on monosynaptic projec-</p><p>tions are sparse in humans, we base our summary on animal studies, with earlier descriptions mostly</p><p>concerning cats, and more recent ones often performed in rats or mice (Figure2, Supplementary file</p><p>1). Connections labeled as sparse in the original papers are not included in this overview.</p><p>Many brain regions lack clear borders. In particular when different species are compared, this may</p><p>lead to some variations in the interpretation of anatomical projections. On top of this, one should also</p><p>take into account that anatomy and physiology do not always match. For instance, the inspiratory</p><p>neurons originally considered to be located in the pre- Bötzinger complex are actually distributed</p><p>around the region of the pre- Bötzinger complex and are partially intermingled with expiratory neurons</p><p>originally considered to be located in more caudal nuclei (Baertsch etal., 2019). When reading this</p><p>review, please note that the use of anatomical names is to help orient oneself, but in reality, borders</p><p>are often fuzzy. Genetic markers may help to define more homogeneous populations of neurons, and</p><p>when this information was available, we mention that in the text and figures.</p><p>Given that the neuronal mechanisms of respiratory rhythm generation are evolutionary well</p><p>conserved (Cinelli etal., 2013), inter- species differences are expected to be relatively minor (Kastner</p><p>and Gauthier, 2008). Important exceptions, however, are the elongation of the pharyngeal region,</p><p>and the development of complex muscle control of pharynx and mouth related to human speech</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 3 of 67</p><p>(Duncker, 2001). Since neural control of speech is outside the scope of this review, this will not be</p><p>further discussed.</p><p>Rhythmic respiration</p><p>Quiet breathing, or eupnea, is a rhythmic alternation between inspiration and passive expiration or</p><p>post- inspiration (Albaiceta etal., 2005; Figure1G). During periods with higher metabolic demand,</p><p>C</p><p>Ambiguus</p><p>nucleus</p><p>Valve</p><p>muscles</p><p>Pump</p><p>muscles</p><p>Thoracic</p><p>spinal</p><p>cord</p><p>Upper</p><p>airways</p><p>Abdomen</p><p>Intercostal</p><p>muscles</p><p>Diaphragm</p><p>Jaw</p><p>Nose</p><p>Tongue</p><p>Scalene muscles</p><p>Parasternal</p><p>intercostal muscles</p><p>External</p><p>intercostal muscles</p><p>Diaphragm</p><p>Sternocleidomastoid muscle</p><p>InspirationA</p><p>D E F</p><p>Sternocleidomastoid muscle</p><p>External intercostal muscles</p><p>Diaphragm</p><p>Rectus abdominis muscle</p><p>Tidal volume</p><p>Eupnea Hyperpnea Singing</p><p>Internal</p><p>intercostal muscles</p><p>Rectus abdominis</p><p>muscle</p><p>External oblique</p><p>muscles</p><p>Internal oblique</p><p>&</p><p>transversus abdominis</p><p>muscles</p><p>ExpirationB</p><p>Facial</p><p>nucleus</p><p>Phrenic</p><p>nucleus</p><p>Trigeminal</p><p>motor</p><p>nucleus</p><p>Hypo-</p><p>glossal</p><p>nucleus</p><p>G</p><p>Vo</p><p>lu</p><p>m</p><p>e</p><p>(l)</p><p>Ex</p><p>pir</p><p>at</p><p>ion</p><p>In</p><p>sp</p><p>ira</p><p>tio</p><p>n</p><p>1.2</p><p>1.0</p><p>0.8</p><p>0.4</p><p>0.6</p><p>0.2</p><p>0.0</p><p>Pressure (cm H2O)</p><p>0 302010 40</p><p>Exp. Exp.Insp. Insp. Exp.Insp. Insp.Exp. Exp. Exp.Insp. Insp. Insp.</p><p>Figure 1. Respiratory muscles and their innervation. (A) The main driving force for inspiration is delivered by the diaphragm in conjunction with the</p><p>external intercostal muscles. Other muscles that can enlarge the chest, such as the parasternal intercostal, sternocleidomastoid and scalene muscles,</p><p>may also contribute. (B) Active expiration involves contraction of the internal intercostal muscles together with abdominal muscles. (C) The pump</p><p>muscles are innervated from the spinal cord, with the phrenic nucleus housing the motor neurons of the diaphragm, and the thoracic spinal cord those</p><p>of the intercostal and abdominal muscles. (D) During regular breathing at rest (eupnea), inspiration is followed by a largely passive form of expiration</p><p>termed post- inspiration or early expiration. During post- inspiration, the abdominal muscles are not (strongly) involved. (E) When the metabolic demand</p><p>is higher, hyperpnea entails the activation of expiratory pump muscles during active expiration. (F) Prolonged post- inspiration, when required assisted</p><p>by active expiration, ensures a longer period with constant outflow of air as exploited by professional singers. (G) Intrapleural pressure- volume curve</p><p>during normal respiration in which the lung compliance is defined as the slope of the dotted line. Schematized data based on Bellani etal., 2018 and</p><p>Pitts etal., 2015 (D–E),Salomoni etal., 2016 (F),and Albaiceta etal., 2005 (G).Exp.=expiration, Insp.=inspiration.</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 4 of 67</p><p>hyperpnea occurs, which entails also active expiration (Pitts et al., 2015; Bellani et al., 2018;</p><p>Figure1D–E). It must be noted that the different respiratory muscles cover different aspects of the</p><p>respiratory cycle. As a result, a clear distinction between passive and active expiration cannot be made.</p><p>For example, during passive expiration, some of the expiratory muscles can be active, and active expi-</p><p>ration encompasses passive elastic contractions as well. In humans, post- inspiration can contribute</p><p>to longer periods of relatively constant air flow as required for speech or singing (MacLarnon and</p><p>Hewitt, 1999; Watson etal., 2012; Salomoni etal., 2016; Figure1F). Here, additional muscles</p><p>become active that are not active during solely post- inspiration. Thus, to what extent the respiratory</p><p>cycle within the brainstem can indeed be divided into rhythmogenic phases or whether these phases</p><p>FNIN</p><p>DN</p><p>LV</p><p>BotC preBotC</p><p>rVRG</p><p>cVRG</p><p>RTN/LPfN</p><p>Mo5</p><p>BPn</p><p>LC</p><p>PAG</p><p>LH</p><p>DR MPBN</p><p>RF</p><p>Ph</p><p>CSC</p><p>TMN</p><p>12N</p><p>NTS</p><p>CR</p><p>BST</p><p>Ce</p><p>Pa</p><p>DM</p><p>Sp5</p><p>Pa5</p><p>Ck</p><p>MDJ PPTg</p><p>Cx</p><p>AAV-RFP</p><p>AAV-retro-GFP</p><p>CN</p><p>IO</p><p>Vest</p><p>PiCo</p><p>7N</p><p>LPBN</p><p>NA</p><p>Limbic system</p><p>Cerebellum-related areas</p><p>Other sensory areasS</p><p>Motor areas</p><p>Central chemoreceptor areasCO2</p><p>Central pattern generators</p><p>Modulatory areas</p><p>Premotor areas</p><p>A</p><p>D</p><p>B</p><p>RN</p><p>FR</p><p>FR100 µmD</p><p>10 µm</p><p>E</p><p>4 µm</p><p>MAO</p><p>B</p><p>C</p><p>C</p><p>KF</p><p>Figure 2. Brain areas involved in subconscious respiratory control. (A) The subcortical areas involved in control of respiration were classified according</p><p>to their main function and plotted at their approximate location on a sagittal projection of the mouse brain. 7N = facial nucleus, 12N=hypoglossal</p><p>nucleus, BotC = Bötzinger complex, BPn = basalpons, BST = bed nucleus of the stria terminalis, Ce = central amygdala, Ck = Clarke’s column, CN</p><p>= cerebellar nuclei, CR = caudal raphe nucleus, CSC = cervical spinal cord, cVRG = caudal ventral respiratory group, Cx = cerebellar cortex, DM =</p><p>dorsomedial hypothalamus, DR = dorsal raphe nucleus, IO = inferior olive, KF = Kölliker- Fuse nucleus, LC = locus coeruleus, LH = lateral hypothalamus,</p><p>LPBN = lateral parabrachial nucleus, LPfN = lateral parafacial nucleus, MDJ = nuclei of the mesodiencephalic junction, Mo5=trigeminal motor</p><p>nucleus, MPBN = medial parabrachial nucleus, NA = nucleus ambiguus, NTS = nucleus of the solitary tract, Pa5=paratrigeminal nucleus, PAG =</p><p>periaqueductalgray, Pa = paraventricular hypothalamus, Ph = phrenic nucleus, PiCo = postinspiratory complex, PPTg = pedunculopontine tegmental</p><p>area, preBotC = pre- Bötzinger complex, RF = reticular formation, RTN = retrotrapezoid nucleus, rVRG = rostral ventral respiratory group, Sp5 = spinal</p><p>trigeminal nucleus, TMN = thoracic motor neurons, Vest = vestibular nuclei. Neural tracing can reveal monosynaptic connections between brain regions,</p><p>as illustrated with an example using an anterograde tracer in the cerebellar nuclei (B;see injection needle in panel A, AAV- RFP, pseudocolored in</p><p>magenta), and a retrograde tracer in the inferior olive (C;AAV- retro- GFP, pseudocolored in yellow). DN = dentate nucleus, FN = fastigial nucleus, IN =</p><p>interposed nucleus, MAO = medial accessory olive. (D) Both tracers can be observed in the MDJ, indicating the presence of monosynaptic projections</p><p>Consequently, we believe that</p><p>integration of behavioral conditions will add to the pathogenesis of respiratory disease.</p><p>Acknowledgements</p><p>The authors wish to thank Dr. Tom Ruigrok, Dr. Jos van der Geest and Ms. Liska Scheffers for discus-</p><p>sions at the start of this project, and Dr. Xiaolu Wang for adapting Figure2B–E. Financial support was</p><p>provided by the Stichting Coolsingel (Grant no. 514 [RSvdG]), the Netherlands Organization for Scien-</p><p>tific Research (NWOALW; CIDZ), the Dutch Organization for Medical Sciences (ZonMW; CIDZ; JJMP),</p><p>BIG (CIDZ), Medical Neuro- Delta (CIDZ), INTENSE LSH- NWO (CIDZ), ERC- adv and ERC- POC (CIDZ),</p><p>Van Raamsdonk- fonds (CIDZ), 3V- Fonds KNAW (CIDZ), Albinism Fonds NIN (CIDZ), Stichting Lijf en</p><p>Leven (JJMP), and by Health Holland to promote public private partnerships (TKI- LSH EMCLSH21017</p><p>[LWJB]).</p><p>Additional information</p><p>Funding</p><p>Funder Grant reference number Author</p><p>Stichting Coolsingel 514 Ruben S van der Giessen</p><p>Nederlandse Organisatie</p><p>voor Wetenschappelijk</p><p>Onderzoek</p><p>ALW Chris I De Zeeuw</p><p>ZonMw Chris I De Zeeuw</p><p>B.I.G. Chris I De Zeeuw</p><p>Medical Neuro-Delta Chris I De Zeeuw</p><p>INTENSE LSH-NWO Chris I De Zeeuw</p><p>European Research</p><p>Council</p><p>Advanced grant Chris I De Zeeuw</p><p>European Research</p><p>Council</p><p>POC Chris I De Zeeuw</p><p>Van Raamsdonk Fonds Chris I De Zeeuw</p><p>Koninklijke Nederlandse</p><p>Akademie van</p><p>Wetenschappen</p><p>3V Fonds Chris I De Zeeuw</p><p>Nederlands Herseninstituut Albinism Fonds Chris I De Zeeuw</p><p>Stichting Lijf en Leven Johan JM Pel</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 36 of 67</p><p>Funder Grant reference number Author</p><p>Health-Holland TKI-LSH EMCLSH21017 Laurens WJ Bosman</p><p>The funders had no role in study design, data collection and interpretation, or the</p><p>decision to submit the work for publication.</p><p>Author contributions</p><p>Friedrich Krohn, Conceptualization, Investigation, Visualization, Writing – original draft, Writing –</p><p>review and editing; Manuele Novello, Investigation, Visualization, Writing – original draft, Writing</p><p>– review and editing; Ruben S van der Giessen, Conceptualization, Funding acquisition, Investigation,</p><p>Visualization, Writing – original draft, Writing – review and editing; Chris I De Zeeuw, Funding acquisi-</p><p>tion, Writing – original draft, Writing – review and editing; Johan JM Pel, Conceptualization, Funding</p><p>acquisition, Investigation, Visualization, Writing – original draft, Project administration, Writing –</p><p>review and editing; Laurens WJ Bosman, Conceptualization, Supervision, Funding acquisition, Inves-</p><p>tigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review</p><p>and editing</p><p>Author ORCIDs</p><p>Friedrich Krohn http://orcid.org/0000-0001-8852-0753</p><p>Manuele Novello http://orcid.org/0000-0002-3622-3092</p><p>Ruben S van der Giessen http://orcid.org/0000-0001-8726-9587</p><p>Chris I De Zeeuw http://orcid.org/0000-0001-5628-8187</p><p>Johan JM Pel http://orcid.org/0000-0001-7618-0413</p><p>Laurens WJ Bosman http://orcid.org/0000-0001-9497-0566</p><p>Additional files</p><p>Supplementary files</p><p>• Supplementary file 1. List of studies demonstrating the existence of monosynaptic projections</p><p>between areas relevant for subconscious control of respiration. Connections that were identified</p><p>as sparse by the authors of these studies are not listed in this table. Note that the list of</p><p>neurotransmitters involved is not complete. 1 Tree shrew (Tupaia belangeri chinensis); 2 Rufous</p><p>horseshoe bat (Rhinolophus rouxi); 3 Rhesus monkey (Macaca mulatta); 4 Crab- eating macaque</p><p>(Macaca fascicularis); 5 Squirrel monkey (Saimiri sciureus). 5- HT = serotonin, A = anterograde,</p><p>aa = amino acids, AAV = adeno associated virus, ACh = acetyl choline, BDA = biotinylated</p><p>dextran amines, Biotinam = biotinamide, CRH = corticotropin- releasing hormone, CTb = cholera</p><p>toxin B subunit, cVRG = caudal part of the ventral respiratory group, DA = dopamine, Degen =</p><p>degeneration, DTR = dextran- Texas red, DY = diamidino yellow, EB = Evans blue, Exc = excitatory</p><p>(not specified which neurotransmitter), E- phys = electrophysiology, FB = fast blue, FG = fluorogold,</p><p>FR = fluoro ruby, GABA = γ-aminobutyric acid, GFP = green fluorescent protein, Glu = glutamate,</p><p>Gly = glycine, HSV = herpes simplex virus, HRP = horseradish peroxidase, Inh = inhibitory (not</p><p>specified which neurotransmitter), m = muscle, MDJ = nuclei of the meso- diencephalic junction, n =</p><p>nucleus or nuclei, NA = noradrenaline / norepinephrine, Nbiotin = neurobiotin, NMB = neuromedin</p><p>B, NT = neurotransmitter, NTS = nucleus tractus solitarii, Optogen = optogenetic stimulation, OXT</p><p>= oxytocin, PHA- L = Phaseolus vulgaris leucoagglutinin, PiCo = post- inspiration complex, PPTg</p><p>= pedunculopontine tegmental nucleus, PI = propidium iodide, POMC = pro- opiomelanocortin,</p><p>Pseudorab = Pseudorabies, R = retrograde, rVRG = rostral part of the ventral respiratory group,</p><p>term = terminalis, TMR = tetramethylrhodamine, VP = vasopressin, WGA = wheat germ agglutinin.</p><p>b – Respiratory control areas affected by pathology Summary of brain regions involved in respiratory</p><p>control and affected by selected diseases or syndromes. 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Sagittal sections from rostral to caudal (see schemes in the lower left corners</p><p>with red rectangles indicating locations of images). FR = fasciculus retroflexus, RN = red nucleus. (E) A neuron (yellow) in the MDJ that projects to the</p><p>inferior olive. Close to the soma of this neuron, a bouton (magenta) of a neuron originating from the cerebellar nuclei can be seen (insets below, imaged</p><p>at two levels 0.7µm apart). Panels B- E originate from a representative mouse and are modified from Figure 7 from Wang etal., 2022.</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 5 of 67</p><p>are just seen at the motor output remains topic of further research. As stated, we discuss in this review</p><p>multiple mechanisms that modulate the rhythmicity of respiration when confronted with respiratory</p><p>challenges, such as a change in air pressure or increase in CO2 concentration (hypercapnia).</p><p>During regular breathing, the respiratory cycle is determined by brainstem central pattern genera-</p><p>tors. Inspiration is triggered by activity of neurons in the pre- Bötzinger complex, most of which fire in</p><p>phase with inspiration and indirectly drive the inspiratory pump muscles (Smith etal., 1991; Guyenet</p><p>and Wang, 2001; Moore etal., 2013; Del Negro etal., 2018; Yang and Feldman, 2018). Inspiration</p><p>may be terminated by activation of the Kölliker- Fuse nucleus, and possibly also the postinspiratory</p><p>I nspiration Post-in</p><p>sp</p><p>ira</p><p>tio</p><p>n</p><p>A</p><p>ctive expiration</p><p>B</p><p>A</p><p>Pre-</p><p>Bötzinger</p><p>complex</p><p>Lateral</p><p>parafacial</p><p>nucleus</p><p>Bötzinger</p><p>complex</p><p>Bötzinger complex (E-AUG)</p><p>Kölliker-Fuse nucleus (I-AUG)</p><p>Kölliker-Fuse nucleus (E-DEC) Abdominal muscles</p><p>Pre-Bötzinger complex (I-AUG) Abdominal muscles</p><p>Lateral parafacial nucleus</p><p>Lateral parafacial nucleus</p><p>Phrenic nerve C Eupnea</p><p>D Hyperpnea</p><p>Exp.Exp. Insp. Insp. Exp. Exp.Insp. Insp.</p><p>Exp. Exp.Insp. Insp. Insp.</p><p>Kölliker-</p><p>Fuse</p><p>nucleus</p><p>Figure 3. Central pattern generators encode the respiratory rhythm. (A) Connections between the pre- Bötzinger</p><p>complex that organizes inspiration, the Kölliker- Fuse nucleus that relates to the inspiration/expiration switch,</p><p>the lateral parafacial nucleus that triggers active expiration, and the Bötzinger complex related to expiration. (B)</p><p>Neuronal activity in the central pattern generators varies during the respiratory cycle. The schematized traces</p><p>represent action potential firing of selected neuronal cell types in relation to activity of the phrenic nerve that</p><p>drives the main inspiratory pump muscle, the diaphragm. From top to bottom: augmenting inspiratory neurons</p><p>(I- AUG) from the pre- Bötzinger complex and the Kölliker- Fuse nucleus, a decreasing expiratory neuron (E- DEC)</p><p>from the Kölliker- Fuse nucleus, and an augmenting expiratory neuron (E- AUG) from the Bötzinger complex. These</p><p>representations are based on in vitro studies of Marchenko etal., 2016 (pre- Bötzinger complex), Ezure and</p><p>Tanaka, 2006 (Kölliker- Fuse nucleus), and Flor etal., 2020 (Bötzinger complex). (C) During eupnea, thus in the</p><p>absence of active expiration, neither the expiratory pump muscles of the abdomen, nor the neurons of the lateral</p><p>parafacial nucleus are active. (D) During hyperpnea, thus when active expiration takes place, abdominal expiratory</p><p>pump muscles are active when the lateral parafacial nucleus neurons produce action potentials. Schematized</p><p>based on in vivo recordings of anesthetized rats by Pagliardini etal., 2011. Insp.=inspiration, Exp.=expiration.</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 6 of 67</p><p>complex can contribute to this (Dutschmann and Herbert, 2006; Anderson etal., 2016). Finally, the</p><p>lateral parafacial nucleus that is silent during eupnea becomes active during active expiration (Pagliar-</p><p>dini etal., 2011; Huckstepp etal., 2015; Del Negro etal., 2018; Figure3). Without input from the</p><p>brainstem, the spinal circuitry cannot organize respiration. It does contribute to sequential contraction</p><p>of thoracic muscles to optimize the inflow of air by adjusting muscle control to body biomechanics</p><p>(Marckwald, 1889; Porter, 1895; Ellenberger and Feldman, 1988; Butler etal., 2014; Shinozaki</p><p>etal., 2019; Jensen etal., 2019).</p><p>Pre-Bötzinger and Bötzinger complexes</p><p>The pre- Bötzinger complex contains a network of neurons generating rhythmic activity that is both</p><p>essential and sufficient to drive inspiration (Smith etal., 1991; Ramirez etal., 1998; Gray etal.,</p><p>2001; Tan etal., 2008; Schwarzacher etal., 2011; Ashhad and Feldman, 2020; Dhingra etal.,</p><p>2020; Figure3B). In rodents, the pre- Bötzinger complex consists of around 3,000 neurons on each</p><p>side of the brain, with approximately equal numbers of excitatory and inhibitory neurons (Wallen-</p><p>Mackenzie etal., 2006; Tan etal., 2008; Yackle etal., 2017). Inspiratory neurons with comparable</p><p>dynamics may also be found in surrounding regions of the ventral respiratory column, pointing toward</p><p>a more diffuse spatiotemporal network than originally described (Baertsch etal., 2019). The rhyth-</p><p>mogenic kernel is formed by somatostatin- negative (SST-) excitatory interneurons (Cui etal., 2016;</p><p>Ashhad and Feldman, 2020). Excitatory neurons in the pre- Bötzinger complex have a refractory</p><p>period that prevents them from generating bursts at a high frequency, and this refractory period can</p><p>be shortened by inhibitory input (Baertsch etal., 2018). Hence, although inhibitory interneurons are</p><p>not essential for generating rhythmicity, they may modulate the breathing frequency and contribute</p><p>to the termination of inspiration (Janczewski etal., 2013; Sherman etal., 2015; Hülsmann etal.,</p><p>2021). The output of the pre- Bötzinger complex is composed of both inhibitory and SST+ excitatory</p><p>neurons.</p><p>Although there are direct projections from the pre- Bötzinger complex to multiple respiratory</p><p>motor nuclei, indirect projections appear to be more common. As such, the phrenic nucleus is</p><p>predominantly targeted via the rostral ventral respiratory group (rVRG) (Wu etal., 2017), and the</p><p>thoracic motor neurons that control abdominal muscles via the caudal ventral respiratory group</p><p>(cVRG) (Gerrits and Holstege, 1996; Yang and Feldman, 2018). In addition, the hypoglossal</p><p>nucleus is principally reached via the parahypoglossal region of the reticular formation (Chamberlin</p><p>etal., 2007; Tan etal., 2010; Yang and Feldman, 2018), and the facial nucleus via the intermediate</p><p>reticular formation (Moore etal., 2004; Koshiya etal., 2014; Yang and Feldman, 2018; Guo etal.,</p><p>2020).</p><p>In addition, there are substantial projections to other respiratory control areas: the Bötzinger</p><p>complex, Kölliker- Fuse nucleus, postinspiratory complex (PiCo), and lateral parafacial nucleus (Tan</p><p>etal., 2010; Koshiya etal., 2014; Yang and Feldman, 2018; Biancardi etal., 2021). Furthermore,</p><p>also the retrotrapezoid nucleus, nucleus tractus solitarii (NTS), lateral and dorsomedial hypothalamus,</p><p>lateral and medial parabrachial nuclei, and periaqueductal gray are targeted (Tan etal., 2010; Koshiya</p><p>etal., 2014; Yang and Feldman, 2018; Biancardi etal., 2021; Trevizan- Baú etal., 2021b). 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DOI: https://doi.org/10.1016/j.</p><p>neuroscience.2021.09.015, PMID: 34582982</p><p>Olson L, Fuxe K. 1971. On the projections from the locus</p><p>reflect sensory</p><p>feedback: while augmenting neurons are inhibited by lung inflation, decrementing neurons are excited</p><p>by it (Manabe and Ezure, 1988; Hayashi etal., 1996). Next to the adjacent pre- Bötzinger complex,</p><p>also other respiratory control centers are innervated by the Bötzinger complex: the Kölliker- Fuse and</p><p>lateral parafacial nuclei (Ezure etal., 2003; Yang etal., 2020; Biancardi etal., 2021).</p><p>The Bötzinger complex also inhibits premotor areas: rVRG and to a lesser extent also cVRG (Jiang</p><p>and Lipski, 1990; Bryant etal., 1993; Ezure, 2004), and directly inhibits motor neurons in the phrenic</p><p>nucleus (Merrill and Fedorko, 1984; Ellenberger etal., 1990b; Tian etal., 1998). Other targets are</p><p>the NTS, lateral parabrachial nucleus and periaqueductal gray (Merrill etal., 1983; Fedorko and</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 7 of 67</p><p>Merrill, 1984; Livingston and Berger, 1989; Smith etal., 1989; Ezure etal., 2003; Trevizan- Baú</p><p>etal., 2021b).</p><p>As the respiratory pattern has to be coordinated with ongoing behavior, the pre- Bötzinger complex</p><p>receives input from many brain regions, like the Kölliker- Fuse nucleus, PiCo, cVRG, NTS, retrotrape-</p><p>zoid nucleus, locus coeruleus, caudal raphe, lateral and paraventricular hypothalamus, central amyg-</p><p>dala, lateral and medial parabrachial nuclei, periaqueductal gray, spinal trigeminal nuclei, and reticular</p><p>formation (Panneton etal., 2006; Rosin etal., 2006; Jones etal., 2016; Hennessy etal., 2017;</p><p>Yang etal., 2020; Liu etal., 2021b; Trevizan- Baú etal., 2021b). The pre- Bötzinger complex receives</p><p>also direct input from the forebrain, including several regions of the neocortex presumably involved in</p><p>voluntary control of respiration, but these connections are relatively sparse (Yang etal., 2020; Trevi-</p><p>zan- Baú etal., 2021a). The inputs of the Bötzinger complex are similar to those of the pre- Bötzinger</p><p>complex, although less widespread (Gang etal., 1995; Supplementary file 1).</p><p>Kölliker-Fuse nucleus</p><p>The pre- Bötzinger complex is not the only area essential for rhythmic respiration. Selective damage</p><p>to the brainstem at the level of the pons leads to impaired transition from inspiration to expira-</p><p>tion, resulting in prolonged periods of inspiration, a condition called apneusis (Marckwald, 1890;</p><p>Lumsden, 1923). This effect was later localized in parts of the parabrachial complex, initially referred</p><p>to as pneumotaxic center, and later as the pontine respiratory group (Cohen and Wang, 1959; Caille</p><p>et al., 1981; Ezure and Tanaka, 2006; Zuperku et al., 2017; Varga et al., 2021). The parabra-</p><p>chial complex is composed of the lateral and medial parabrachial nuclei, that have predominantly</p><p>ascending projections carrying sensory information, and the Kölliker- Fuse nucleus that primarily</p><p>targets subcortical structures (Fulwiler and Saper, 1984). Accordingly, of the parabrachial complex</p><p>it is mainly the Kölliker- Fuse nucleus that influences the switch from inspiration to expiration (Dama-</p><p>sceno etal., 2014; Dutschmann etal., 2021; Figure3B). Neurons of the Kölliker- Fuse nucleus show</p><p>activity related to specific phases of respiration, with most neurons being active during inspiration;</p><p>these latter neurons abruptly stop firing at the end of inspiration, marking the inspiration- expiration</p><p>transition (Dick etal., 1994; Ezure and Tanaka, 2006; Dutschmann etal., 2021). A bilateral block of</p><p>activity in the Kölliker- Fuse nucleus prolonged the inspiratory activity of the phrenic nerve in an in situ</p><p>preparation, but did not completely block the termination of inspiratory activity (Dutschmann etal.,</p><p>2021), which would be in line with a prominent, but not exclusive role of the Kölliker- Fuse nucleus for</p><p>the termination of inspiration.</p><p>The Kölliker- Fuse nucleus receives input from the pre- Bötzinger and Bötzinger complexes (Ezure</p><p>etal., 2003; Tan etal., 2010; Yang and Feldman, 2018), and from several central chemoreceptor</p><p>areas: the NTS (Loewy and Burton, 1978; Herbert etal., 1990; McGovern etal., 2015b), retro-</p><p>trapezoid nucleus (Rosin et al., 2006; Bochorishvili et al., 2012; Silva et al., 2016b), and cere-</p><p>bellar fastigial nucleus (Fujita etal., 2020). In addition, the Kölliker- Fuse nucleus also receives input</p><p>from the rVRG (Lipski et al., 1994; Yokota et al., 2016), cVRG (Holstege, 1989; Jones et al.,</p><p>2016), periaqueductal gray (Trevizan- Baú etal., 2021b), spinal trigeminal nucleus (Panneton etal.,</p><p>2006; Zhang etal., 2018), paratrigeminal nucleus (Saxon and Hopkins, 1998), pedunculopontine</p><p>tegmental nucleus (PPTg) (Lima etal., 2019b), and vestibular nuclei (Shi etal., 2021). Finally, there</p><p>are descending inputs from the lateral, dorsomedial and paraventricular hypothalamus (Yokota etal.,</p><p>2016; Trevizan- Baú etal., 2021a).</p><p>Glutamatergic projections directly and indirectly (via the rVRG) target the phrenic nucleus (Ellen-</p><p>berger etal., 1990b; Yokota etal., 2004; Yokota etal., 2007; Song etal., 2012a; Geerling etal.,</p><p>2017), as well as the ambiguus, hypoglossal and facial nuclei (Núñez- Abades etal., 1990; Yokota</p><p>etal., 2007; Song etal., 2012a; Yokota etal., 2015; Geerling etal., 2017). The latter connec-</p><p>tions allow premotor neurons in the Kölliker- Fuse nucleus to constrict valve muscles, reducing outflow</p><p>during post- inspiration (Dutschmann and Herbert, 2006).</p><p>Further excitatory projections target, in addition to the other nuclei of the parabrachial complex</p><p>(Song etal., 2012a; Geerling etal., 2017), the pre- Bötzinger complex (Yang etal., 2020), PiCo</p><p>(Oliveira etal., 2021), and lateral parafacial nucleus (Biancardi etal., 2021). Also the cVRG (Gerrits</p><p>and Holstege, 1996; Song etal., 2012a), reticular formation (Geerling etal., 2017), retrotrape-</p><p>zoid nucleus, NTS, and periaqueductal gray (Fulwiler and Saper, 1984; Song etal., 2012a; Geer-</p><p>ling etal., 2017; Trevizan- Baú etal., 2021b) receive glutamatergic input. The caudal part of the</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 8 of 67</p><p>Kölliker- Fuse nucleus sends inhibitory projections mainly to the sensory trigeminal nucleus, but also</p><p>to the dorsomedial hypothalamus (Geerling etal., 2017). Finally, there are projections to the raphe</p><p>nuclei (Hermann etal., 1997; Peyron etal., 2018), vestibular nuclei (Shi etal., 2021), and cerebellar</p><p>cortex (Fu etal., 2011).</p><p>Post-inspiratory complex</p><p>Recently, a second brain region involved in controlling post- inspiration has been identified in the</p><p>ventral part of the intermediate reticular formation: the postinspiratory complex, or PiCo, consisting</p><p>of cholinergic neurons (Anderson etal., 2016; Toor etal., 2019; Oliveira etal., 2021). Isolated in a</p><p>tissue slice, the PiCo can generate rhythmic activity that peaks during post- inspiration, and thus poten-</p><p>tially contributes to a biphasic (pre- Bötzinger complex – PiCo) or triphasic (pre- Bötzinger complex –</p><p>PiCo – parafacial nucleus) oscillator controlling respiration (Anderson etal., 2016; Anderson and</p><p>Ramirez, 2017). Optogenetic stimulation in vivo confirmed that PiCo activity can prolong post-</p><p>inspiration (Oliveira etal., 2021).</p><p>The role of the PiCo in controlling post- inspiration has not yet been fully investigated (Hülsmann,</p><p>2021; Ashhad etal., 2022). Although this is not a proof against a coordinating role of the PiCo for</p><p>post- inspiration, systematic recordings in a whole- brainstem preparation found widespread activity</p><p>during post- inspiration, but more in the pontine region than focused in the area of the PiCo (Dhingra</p><p>etal., 2020). 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Respiratory- related neurons of the fastigial</p><p>likely that the PiCo is involved in the neural control</p><p>of post- inspiration, but probably more as part on an integrated network than as primary pattern</p><p>generator.</p><p>The PiCo receives strong input from the Kölliker- Fuse nucleus and periaqueductal gray, but there</p><p>are also substantial connections from the caudal and intermediate NTS and the hypothalamic para-</p><p>ventricular nucleus (Oliveira etal., 2021). Also the pre- Bötzinger complex projects to the PiCo (Yang</p><p>and Feldman, 2018). As far as we are aware, there are no systematic studies on PiCo efferents, but</p><p>projections to the pre- Bötzinger complex and retrotrapezoid nucleus have been demonstrated (Lima</p><p>etal., 2019b; Yang etal., 2020).</p><p>Lateral parafacial nucleus</p><p>At the end of the respiratory cycle, the lateral parafacial nucleus can trigger active expiration by</p><p>recruiting expiratory abdominal muscles via the cVRG (Janczewski and Feldman, 2006; Huckstepp</p><p>etal., 2015; Silva etal., 2016a; Pisanski and Pagliardini, 2019). In the literature, the term parafacial</p><p>respiratory group is sometimes used as synonym for the lateral parafacial nucleus, or for the combi-</p><p>nation of the lateral and the ventral parafacial nucleus, or even for the latter together with the retro-</p><p>trapezoid nucleus (Onimaru and Homma, 2003; Huckstepp etal., 2015; Pisanski and Pagliardini,</p><p>2019; Biancardi etal., 2021).</p><p>In embryonic and newborn rodents, the lateral parafacial nucleus is rhythmically active at rest</p><p>(Onimaru and Homma, 2003; Thoby- Brisson etal., 2009), but this activity wanes during early devel-</p><p>opment (Oku etal., 2007; van der Heijden and Zoghbi, 2020), and in adults the lateral parafacial</p><p>nucleus is generally silent during eupnea, but rhythmically active during hyperpnea (Pagliardini etal.,</p><p>2011; Huckstepp etal., 2015; de Britto and Moraes, 2017; Figure3C–D). The inactivity at rest</p><p>could be due to tonic inhibition from the medial NTS (Silva etal., 2019). Excitatory input from the</p><p>commissural NTS, conveying chemosensitive input from the carotid bodies, can activate neurons in</p><p>the lateral parafacial nucleus during periods with elevated blood CO2 levels (Morris et al., 2018;</p><p>Silva etal., 2019). In addition, the parafacial nucleus receives direct input from chemoreceptors in</p><p>the adjacent retrotrapezoid nucleus (Zoccal etal., 2018; Biancardi etal., 2021). Furthermore, input</p><p>comes also from the pre- Bötzinger and Bötzinger complexes, rVRG, Kölliker- Fuse nucleus, reticular</p><p>formation, caudal raphe, lateral and medial parabrachial nuclei, periaqueductal gray, PPTg and vestib-</p><p>ular nuclei (Biancardi etal., 2021).</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 9 of 67</p><p>Sensory feedback</p><p>To adapt the depth of ventilation to the metabolic state, the blood gas balance is continuously moni-</p><p>tored. At the same time, sensory systems of the airways and lungs, consisting of thermo-, mechano-,</p><p>and chemoreceptors, survey ongoing respiration and detect environmental irritants and inflamma-</p><p>tory mediators (Sant’Ambrogio etal., 1983; Lee and Yu, 2014). Muscle spindles give feedback on</p><p>posture and respiratory muscle performance (Nakayama etal., 1998). Altogether, sensory feedback</p><p>affects ventilatory control, and can trigger respiratory reflexes aimed at maintaining homeostasis upon</p><p>adverse events. In addition, also hormones can modulate respiratory behavior.</p><p>Chemoreception</p><p>Chemoreceptors monitor the partial pressures of O2 (pO2) and CO2 (pCO2) in blood and cerebrospinal</p><p>fluid. Since CO2 reacts with water to form HCO3</p><p>- and H+, increased pCO2 leads to acidosis that can</p><p>cause adverse effects on tissue structures, and may result in headaches, delirium and eventually coma</p><p>(Cummins etal., 2020). Regulation of pCO2 is therefore, next to that of pO2, of great importance,</p><p>and a major drive for the level of ventilation (Miescher- Rüsch, 1885; Haldane and Priestley, 1905).</p><p>The concentrations of both gasses are continuously measured by peripheral chemoreceptors in the</p><p>carotid bodies (Gonzalez etal., 1994; Milsom and Burleson, 2007; Cummins etal., 2020; Ortega-</p><p>Sáenz and López- Barneo, 2020). The carotid bodies project mainly to the NTS (Claps and Torrealba,</p><p>1988; Finley and Katz, 1992; Mifflin, 1992; Zera etal., 2019), but also to the cVRG (Finley and</p><p>Katz, 1992).</p><p>Acidosis can also be caused by inflammation, ischemia or defective acid containment. Conse-</p><p>quently, acid sensing is not restricted to respiratory control and has evolved as an important property</p><p>of neurons with unmyelinated and thinly myelinated fibers (Canning and Spina, 2009). Only those</p><p>areas that sense pH changes and directly affect ventilation are considered to be central chemore-</p><p>ceptor areas. In this respect, most attention has been given to the retrotrapezoid nucleus, but also the</p><p>NTS, locus coeruleus, raphe nuclei, lateral hypothalamus, and cerebellar fastigial nucleus are central</p><p>chemoreceptor areas (Coates etal., 1993; Nattie, 1999; Nattie and Li, 2002; Xu and Frazier, 2002;</p><p>Putnam etal., 2004; Guyenet etal., 2008; Dean and Putnam, 2010; Li etal., 2013; Figure4A).</p><p>Central chemoreceptors</p><p>Several molecular mechanisms for central chemoreception have been proposed (Gourine and Dale,</p><p>2022). First, in astrocytes, increased levels of HCO3</p><p>- can activate the electroneutral Na+/HCO3</p><p>- co- trans-</p><p>porter NBCn1 (SLC4A7), causing Na+ influx that in turn activates the astrocytic Na+/Ca2+ exchanger</p><p>Ncx103 (SLC8A1- 3; Turovsky etal., 2016). The resulting increase in intracellular Ca2+ triggers ATP</p><p>release (Gourine etal., 2005; Gourine etal., 2010). Purinergic receptors on nearby neurons are acti-</p><p>vated by ATP, leading to neuronal excitation (Gourine etal., 2005; Figure4B–C).</p><p>Second, inward- rectifier K+ (Kir) channels can be inhibited by a decrease in pH, and trigger depolar-</p><p>ization and consequently ATP release by astrocytes (Wenker etal., 2010; Figure4C).</p><p>A third mechanism, one that is independent of pH changes, involves the ability of CO2 to induce</p><p>conformational changes in the connexin- hemichannel Cx26 located in gap junctions between glial</p><p>cells, rendering Cx26 permeable to ATP (Bevans and Harris, 1999; Huckstepp etal., 2010; Meigh</p><p>etal., 2013; van de Wiel etal., 2020; Figure4E). Later studies revealed the interaction between CO2</p><p>and Cx26 to be more complicated, and probably context- dependent (Nijjar etal., 2021).</p><p>In addition to glial- mediated chemoreception, also neurons express acid- sensitive ion channels</p><p>(ASICs) and receptors (Canning and Spina, 2009). Among these are some members of the family</p><p>of inwardly rectifying K2P channels (Lesage and Barhanin, 2011; Sepúlveda etal., 2015), such as</p><p>TASK1 and TASK3 that are co- expressed with ASIC1 in the ventrolateral medulla, and contribute to</p><p>central chemoreception in rats (Wang etal., 2018). Another family member is the TASK- 2 K+ leak</p><p>channel, whose absence leads to impaired ventilatory responses to hypercapnia (Gestreau et al.,</p><p>2010; Bayliss etal., 2015; Figure4D).</p><p>The KCNA1 gene encodes the α subunit of Kv1.1 voltage- gated potassium channels that show</p><p>particularly strong expression in hippocampus, cerebellum, neocortex and peripheral nerves</p><p>(D’Adamo etal., 2014; Ovsepian etal., 2016). 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DOI: https://doi.org/10.1152/</p><p>japplphysiol.00914.2004, PMID: 15557013</p><p>Yu L, Zhang XY, Zhang J, Zhu JN, Wang JJ. 2010. Orexins excite neurons of the rat cerebellar nucleus</p><p>interpositus via orexin 2 receptors in vitro. Cerebellum 9:88–95. DOI: https://doi.org/10.1007/s12311-009-</p><p>0146-0, PMID: 19921532</p><p>Yu RB, Huang CC, Chang CH, Wang YH, Chen JW. 2021. Prevalence and patterns of tongue deformation in</p><p>obstructive sleep apnea: A whole- night simultaneous ultrasonographic</p><p>sudden unexpected death in epilepsy (SUDEP), while also showing progressive respiratory dysfunc-</p><p>tion (Simeone etal., 2018; D’Adamo etal., 2020; Paulhus etal., 2020). As respiratory dysfunction</p><p>is hypothesized to be a primary risk factor for susceptibility to the cardiorespiratory dysfunction in</p><p>epilepsy, this could reveal a new role for KCNA1 channelopathies in the regulation of basal respiratory</p><p>physiology (Dhaibar etal., 2019).</p><p>Vagal sensory input</p><p>The lungs and airways, in particular the larynx, are lined with sensory receptors associated with the</p><p>nervus vagus (Mortola etal., 1975; Lee and Yu, 2014; Mazzone and Undem, 2016; Kupari etal.,</p><p>A</p><p>B</p><p>D</p><p>C</p><p>CVessel</p><p>+</p><p>+ +</p><p>+</p><p>CO2 + H2O → HCO3 + H+</p><p>HCO3</p><p>HCO3 Na+ Ca2+</p><p>ATP</p><p>ATP</p><p>Na+</p><p>Na+</p><p>Na+</p><p>K+</p><p>K+</p><p>K+</p><p>K+</p><p>K+</p><p>K+Vm</p><p>Ca2+</p><p>CO2</p><p>NBCn1</p><p>Astrocytes</p><p>Neuron</p><p>Astrocyte</p><p>Neuron</p><p>ASIC1 TASK1</p><p>TASK3</p><p>Vessel</p><p>Ncx103 Kir</p><p>+</p><p>E 100 nm</p><p>E</p><p>D</p><p>NTS</p><p>CO2</p><p>Fastigial</p><p>nucleus</p><p>CO2</p><p>Retro-</p><p>trapezoid</p><p>nucleus</p><p>CO2</p><p>Locus</p><p>coeruleus</p><p>CO2</p><p>Caudal</p><p>raphe</p><p>CO2</p><p>Lateral</p><p>hypo-</p><p>thalamus</p><p>CO2</p><p>Carotid</p><p>bodies</p><p>CO2O2</p><p>Dorsal</p><p>raphe</p><p>CO2</p><p>CO2 + H2O → HCO3 + H+</p><p>Figure 4. Respiratory chemoreception. (A) Connections between the carotid bodies and the central</p><p>chemoreceptor areas. (B) Astrocytes are in direct contact with blood vessels and neurons. (C) Chemoreceptor</p><p>pathways in astrocytes triggering ATP release that can activate nearby neurons. (D) Chemoreceptor pathways in</p><p>neurons, based on activation of Na+ channelsand inward- rectifier K+ channels. (E) Gap junctions between glial</p><p>cells, as shown here in the cerebellar cortex of a mouse (yellow arrows), can contribute to central chemoreception.</p><p>In particular, the conductivity of gap junctions composed of Cx26 depends on pH. Previously unpublished electron</p><p>microscopic image from our lab.</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 11 of 67</p><p>2019). Flow receptors sense air temperature, which is typically colder for inhaled than for exhaled air</p><p>(Sant’Ambrogio etal., 1983), and drive receptors measure the laryngeal wall pressure that correlates</p><p>with its conductivity (Horner, 2012). Flow and drive receptors are active during each breath (Sant’Am-</p><p>brogio etal., 1983), while other mechano- and chemoreceptors are only activated during adverse</p><p>conditions, such as an obstruction, the presence of irritants, or increased CO2 concentrations (Lee and</p><p>Yu, 2014). Sensory information from the distal airways is transferred via the nodose ganglion to the</p><p>NTS, while that of the proximal airways goes predominantly via the jugular ganglion to the paratri-</p><p>geminal nucleus (McGovern etal., 2015a; McGovern etal., 2015b; Kim etal., 2020).</p><p>Vagal stretch receptors, associated with Aβ fibers, can be subdivided into slowly and rapidly</p><p>adapting receptors: SARs and RARs, respectively. SARs sense inflation and can stay activated for</p><p>sustained periods, while RARs are more sensitive to acute changes in pressure (Davenport etal.,</p><p>1981; Kaufman etal., 1982; Mazzone and Undem, 2016). Although all RARs rapidly adapt to a</p><p>persistent mechanical stimulus, a subset of them, the so- called irritant receptors, can remain acti-</p><p>vated by specific chemicals for a prolonged period (Sant’Ambrogio, 1982). Environmental irritants</p><p>and inflammatory mediators can trigger activity of unmyelinated C fibers, while localized mechanical</p><p>stimuli and acid can activate thinly myelinated Aδ fibers that are also known as cough receptors, and</p><p>that are located in the airway epithelium and mucosa (Coleridge and Coleridge, 1984; Canning</p><p>etal., 2004; Mazzone etal., 2009; Grace etal., 2012; Canning etal., 2014; Mazzone and Undem,</p><p>2016).</p><p>Cough and expiration reflexes</p><p>Coughing is a vital action to clear the airways. Coughing involves first inspiration, then obstruction of</p><p>airways to build up pressure, and subsequent explosive expulsion of air. Ineffective cough reflexes,</p><p>for example in patients with dementia, can lead to lethal aspiration pneumonia (Widdicombe, 1995;</p><p>Mutolo, 2017; Sykes and Morice, 2021). Inversely, the relatively common condition of chronic cough,</p><p>affecting more than 5% of the adult population, is thought to be caused by hypersensitivity to airway</p><p>stimulation (Morice etal., 2020).</p><p>The cough reflex is typically triggered by stimulation of the cough receptors and possibly also by</p><p>activation of C fibers in the airways (Ludlow, 2015; Mutolo, 2017). Mechanical stimulation of the vocal</p><p>cords can trigger the expiration reflex, which resembles cough without the initial inspiration (Korpas</p><p>and Jakus, 2000; Sant’Ambrogio and Widdicombe, 2001; Tatar etal., 2008; Ludlow, 2015).</p><p>Stimulation of irritant receptors in the upper airways can evoke a cough reflex via activation of the</p><p>paratrigeminal nucleus, and this reflex can be suppressed by the submedial thalamic nucleus and the</p><p>upstream ventrolateral orbital cortex (Mazzone etal., 2020). In the periaqueductal gray, the excit-</p><p>atory drive from the paratrigeminal nucleus and the inhibitory input from the ventrolateral orbital</p><p>cortex come together (McGovern et al., 2015b). The periaqueductal gray is hence an important</p><p>intermediate between the forebrain and the cVRG (Holstege, 1989; Subramanian etal., 2008; Chen</p><p>etal., 2022). The cVRG itself is essential for the cough reflex (Mutolo, 2017; Cinelli etal., 2020), as it</p><p>can activate both expiratory motor neurons in the thoracic spinal cord, controlling abdominal muscles,</p><p>and in the ambiguus nucleus, controlling laryngeal muscles (Figure5F).</p><p>Stimulation of the lower airways or the lungs activates RAR relay neurons in the NTS. These neurons</p><p>receive also input from various other sources that can contribute to suppression or facilitation of</p><p>coughing (Mutolo, 2017). Thalamocortical loops can further modulate coughing and exert voluntary</p><p>control (Ando etal., 2016). Like the paratrigeminal nucleus, the NTS innervates the cVRG (Gerrits</p><p>and Holstege, 1996). In addition, the NTS affects also the phrenic nucleus, directly as well as indi-</p><p>rectly via the rVRG (Ezure and Tanaka, 1996; Wu etal., 2017). These connections are complemented</p><p>with direct output to the ambiguus nucleus from both the paratrigeminal nucleus and the NTS (Caous</p><p>etal., 2001; de Sousa Buck etal., 2001; Kawai, 2018; Figure5F).</p><p>Sneeze reflex</p><p>In the nasal mucosa, irritant receptors expressing Trpv1, a capsaicin- sensitive cation ion channel, that</p><p>can be activated by histamine H1R receptors (Shim etal., 2007), are present on thin sensory fibers of</p><p>the ethmoidal nerve that terminates in the sneeze- evoking region (Lucier and Egizii, 1986; Nonaka</p><p>etal., 1990; Seijo- Martínez etal., 2006; Li etal., 2021). The sneeze- evoking region is a dedicated</p><p>part of the spinal trigeminal nucleus that projects to the cVRG (Li etal., 2021).</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 12 of 67</p><p>Dorso-</p><p>medial</p><p>hypothal.</p><p>Para-</p><p>ventricular</p><p>hypothal.</p><p>Central</p><p>amygdala BNST</p><p>Pre-</p><p>Bötzinger</p><p>complex</p><p>Peri-</p><p>aqueductal</p><p>gray</p><p>PPTg</p><p>MPBN</p><p>LPBN</p><p>A</p><p>Rostral</p><p>Intermediate</p><p>Caudal</p><p>AP</p><p>Fourth</p><p>ventricle</p><p>NTS</p><p>Rostral</p><p>Caudal</p><p>Intermediate</p><p>Caudal</p><p>Dorsal</p><p>Ventral</p><p>250 µm</p><p>Gelatinous</p><p>Com</p><p>m</p><p>.</p><p>IV</p><p>Central</p><p>Medial</p><p>Interm.Ventral</p><p>Ventro-</p><p>lateral</p><p>Dorsolateral</p><p>Dorsomedial</p><p>Medial</p><p>Inter-</p><p>mediate</p><p>Ventral</p><p>Inter-</p><p>stitialVentro-</p><p>lateral Central</p><p>AP</p><p>B</p><p>Modulatory areas</p><p>C Pattern generators</p><p>Lateral</p><p>hypo-</p><p>thalamus</p><p>CO2</p><p>Central chemoreceptor areas Limbic system</p><p>Motor areas</p><p>Phrenic</p><p>nucleus</p><p>Trigeminal</p><p>motor</p><p>nucleus</p><p>Facial</p><p>nucleus</p><p>Hypo-</p><p>glossal</p><p>nucleus</p><p>Ambiguus</p><p>nucleus</p><p>Pre-</p><p>Bötzinger</p><p>complex</p><p>Lateral</p><p>parafacial</p><p>nucleus</p><p>PiCo</p><p>Input from NTS</p><p>Output to NTS</p><p>Retro-</p><p>trapezoid</p><p>nucleus</p><p>CO2</p><p>Locus</p><p>coeruleus</p><p>CO2</p><p>Dorsal</p><p>raphe</p><p>CO2</p><p>Caudal</p><p>raphe</p><p>CO2</p><p>Spinal</p><p>trigeminal</p><p>nucleus</p><p>Para-</p><p>trigeminal</p><p>nucleus</p><p>Sensory regions</p><p>Bötzinger</p><p>complex</p><p>Sensorimotor areas</p><p>Inferior</p><p>olive</p><p>Cerebellar</p><p>cortex</p><p>Vestibular</p><p>nuclei</p><p>cVRG</p><p>rVRG</p><p>Premotor areas</p><p>FD Coughing reflex</p><p>Respiration</p><p>Capsaicin</p><p>Brady-</p><p>pnea</p><p>Brady-</p><p>cardiaNTS</p><p>POMC</p><p>CO2</p><p>E Cardiorespiratory regulation</p><p>Peri-</p><p>aqueductal</p><p>gray</p><p>Para-</p><p>trigeminal</p><p>nucleus</p><p>Submedial</p><p>thalamus</p><p>Ventrolat.</p><p>orbital</p><p>cortex</p><p>Thalamus Cerebral</p><p>cortex</p><p>Larynx</p><p>Upper airways</p><p>Lungs</p><p>Lower airways</p><p>Nodose</p><p>ganglion</p><p>rVRG Phrenic</p><p>nucleus</p><p>NTS</p><p>CO2</p><p>cVRG</p><p>Abdom</p><p>en</p><p>D</p><p>iaphragm</p><p>Ambiguus</p><p>nucleus</p><p>Larynx</p><p>Ambiguus</p><p>nucleus</p><p>Thoracic</p><p>spinal</p><p>cord</p><p>Jugular</p><p>ganglion</p><p>C fibers</p><p>RARs</p><p>+</p><p>P</p><p>cells</p><p>RAR</p><p>cells</p><p>SARs</p><p>+</p><p>+</p><p>RAR receptor</p><p>C fiber</p><p>SAR receptor</p><p>Kölliker-</p><p>Fuse</p><p>nucleus</p><p>Figure 5. The nucleus of the solitary tract and vagal afferents. Schematic drawings of the nucleus of the solitary tract (NTS) in relation to the area</p><p>postrema (AP) and the fourth ventricle (IV). Dorsal (A) and coronal views at intermediate and caudal levels (B). (C) Brain regions that project to, or get</p><p>input from the NTS. With most areas, bidirectional connections exist (cyan dots: areas innervated by NTS neurons; black dots: areas with neurons</p><p>innervating the NTS). (D) Heterogeneity in vagal afferents. Capsaicin can, as a pulmonary irritant, evoke activity of C fibers, but not of rapidly or</p><p>Figure 5 continued on next page</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 13 of 67</p><p>Postural feedback</p><p>The external and internal intercostal muscles assist with, respectively, expansion and contraction</p><p>of the rib- cage during breathing (Figure1A–E). In addition, the intercostal muscles exert postural</p><p>control, and they combine their respiratory and postural activity in a superposed manner (Rimmer</p><p>etal., 1995). Single intercostal 1a afferents project to the region of Clarke’s column, to the inter-</p><p>costal motor nucleus, and to the intermediate regions, conveying sensory feedback originating from</p><p>muscle spindles in the intercostal muscles (Nakayama etal., 1998). From Clarke’s column, informa-</p><p>tion is projected to the cerebellar cortex via the spinocerebellar tract, originating from two types</p><p>of respiration- related neurons in the lower thoracic segments (T9- T12). This spinocerebellar tract</p><p>contains uncrossed as well as crossed ascending axons that play different roles in transmitting signals</p><p>between the spinal cord and the cerebellum (Tanaka and Hirai, 1994). Rhythmic activity in uncrossed</p><p>spinocerebellar tract neurons, located in and around Clarke’s column, reflects afferent activity from</p><p>the chest wall, whereas that of crossed neurons, located in laminae VII and VIII, reflect descending</p><p>influence from the respiratory centers with or without peripheral influences (Matsushita etal., 1979;</p><p>Tanaka and Hirai, 1994). It has been suggested that the cerebellum uses the posture- related infor-</p><p>mation of the thoracic spinocerebellar tract neurons to adjust posture or coordination of whole body</p><p>movements (Tanaka and Hirai, 1994).</p><p>Hormonal regulation of respiration</p><p>Several hormones can affect development and metabolism, and thus have an indirect effect on respi-</p><p>ration. Thyroid hormones, for instance, are critical for the development of the respiratory system,</p><p>and their dysfunction can lead to respiratory failure, including the respiratory distress syndrome (Pei</p><p>etal., 2011; Rousseau etal., 2021). Hormones with a specific role in respiratory control are discussed</p><p>below.</p><p>Sex hormones</p><p>Progesterone, estradiol and testosterone can all affect respiratory parameters (White etal., 1985),</p><p>and these effects could help explain differences in respiratory behavior between males and females,</p><p>as well as during different life stages (Gargaglioni etal., 2019; LoMauro and Aliverti, 2021). Indeed,</p><p>sex hormone receptors are widely distributed in the brain, including central chemoreceptor areas</p><p>(Gargaglioni etal., 2019; LoMauro and Aliverti, 2021), certain respiratory motor neurons, such as</p><p>the hypoglossal and phrenic nuclei (Behan and Thomas, 2005), and cerebellar Purkinje cells (Perez-</p><p>Pouchoulen etal., 2016). Progesterone levels correlate with the muscle tone of the genioglossus</p><p>muscle, and thus with upper airway rigidity, which could play a role in the reduced occurrence of</p><p>obstructive sleep apnea in females when compared to males (Popovic and White, 1998).</p><p>Leptin</p><p>Leptin is primarily secreted by adipocytes. An increase in adipose tissue therefore leads to more leptin</p><p>secretion, which results in increased breathing activity (Chang etal., 2013; Bassi etal., 2016; Gauda</p><p>etal., 2020). Leptin can activate a specific subset of excitatory neurons in the NTS projecting to respi-</p><p>ratory premotor neurons in the rVRG, as well as to the dorsomedial hypothalamus (Do etal., 2020).</p><p>Next to the direct projection from the NTS to the rVRG, an indirect pathway via the lateral parabra-</p><p>chial nucleus to the pre- Bötzinger complex is also likely to contribute to the impact of leptin on respi-</p><p>ratory frequency (Yu etal., 2022). The dorsomedial hypothalamus, which itself also contains leptin</p><p>slowly adapting receptors (RAR and SAR, respectively). The latter two show phasic activity during regular breathing. Schematic drawing of action</p><p>potential firing based on data presented in Ho etal., 2001. (E) Pro- opiomelanocortin- expressing (POMC) neurons of the NTS project to the pre-</p><p>Bötzinger complex and to cardiac vagal motor neurons in the ambiguus nucleus. Via these pathways, they can reduce inspiration and cardiac function,</p><p>respectively. (F) Coughing can be triggered by sensing an irritant via vagal projections from the larynx or upper airways via the jugular ganglion to</p><p>the paratrigeminal nucleus, or from the lungs or lower airways via the nodose ganglion to the NTS. Distinct types of vagal fibers differentially affect</p><p>RAR relay neurons, with SARs inhibiting pump neurons (P cells). The motor neurons of expiratory muscles are directly and indirectly activated from the</p><p>paratrigeminal nucleus and the NTS. A specific cortical circuit for inhibiting reflexive coughing involving the submedial thalamus and the ventrolateral</p><p>orbital cortex has been described, next to more general thalamo- cortical pathways that can modulate coughing. The latter pathways can use different</p><p>connections to premotor nuclei (indicated with dotted lines).</p><p>Figure 5 continued</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 14 of 67</p><p>receptors, can contribute to upper airway control during respiration (Yao etal., 2016). The impact</p><p>of the leptin- mediated pathways may be compromised in obesity, as leptin resistance can contribute</p><p>to the development of obesity hypoventilation syndrome and central sleep apnea (O’Donnell etal.,</p><p>2000; Yao etal., 2016; Framnes and Arble, 2018).</p><p>Full- length leptin receptors (LEPRB) are not restricted to the NTS and dorsomedial hypothalamus,</p><p>but can also be found in the carotid bodies, neocortex, substantia nigra and cerebellum (Guan etal.,</p><p>1997; Gavello etal., 2016). Although it is not clear whether these all affect respiratory control, it has</p><p>been shown that activation of leptin receptors in the carotid bodies can affect breathing and induce</p><p>ventilatory response to hypoxia (Caballero- Eraso etal., 2019).</p><p>Hyperventilation</p><p>Not only increased metabolic activity, but also emotional arousal can cause an increase in the level</p><p>of ventilation. While such a stress- induced reaction makes sense as preparation for a fight or flight</p><p>reaction, it can derail during a panic attack (Suess etal., 1980; Meuret etal., 2017). In the absence</p><p>of increased metabolic demands, hyperventilation induces a decrease in pCO2, which increases blood</p><p>pH (Gardner, 1996). Hyperventilation can be associated with several symptoms of panic, including</p><p>shortness of breath, heart racing, dizziness, and fear of dying (Gardner, 1996; Meuret etal., 2017).</p><p>Although hyperventilation is typically triggered by stress, anxiety or panic,</p><p>in rare cases it can also</p><p>have a neurological cause, and central neurogenic hyperventilation is often associated with pontine</p><p>damage (Plum and Swanson, 1959; Tarulli etal., 2005).</p><p>Central chemoreceptor areas</p><p>Retrotrapezoid nucleus</p><p>The retrotrapezoid nucleus is considered as the main central chemoreceptor area, and inhibition of its</p><p>activity reduces the ventilatory response to hypercapnia (Mulkey etal., 2004; Marina etal., 2010;</p><p>Burke etal., 2015; Ruffault etal., 2015), while optogenetic stimulation of the retrotrapezoid nucleus</p><p>can increase the breathing rate by reducing the duration of expiration (Abbott etal., 2009; Abbott</p><p>etal., 2011; Burke etal., 2015; Souza etal., 2020). Cholinergic input, probably from the PPTg and</p><p>the PiCo, can increase the activity of chemoreceptors (Sobrinho etal., 2016; Lima etal., 2019b),</p><p>while serotonergic input from the caudal and dorsal raphe can enhance the chemosensitive response</p><p>in the retrotrapezoid nucleus (Rosin etal., 2006; Brust etal., 2014; Wu etal., 2019; Leirão etal.,</p><p>2021).</p><p>The retrotrapezoid nucleus consists in mice of around 700 Phox2b- positive cells located ventro-</p><p>lateral to the facial nucleus. The locations of these neurons partially overlap with those of the lateral</p><p>parafacial nucleus (Smith etal., 1989; Onimaru and Homma, 2003; Ramanantsoa etal., 2011; Shi</p><p>etal., 2017). The retrotrapezoid nucleus houses also around 200 biochemically and morphologically</p><p>different neurons that lack CO2- sensitivity, and that could be related to sighing via their direct projec-</p><p>tion to the pre- Bötzinger complex (Li etal., 2016; Shi etal., 2017).</p><p>Next to pCO2, also sensory input relayed via the caudal and commissural parts of the NTS (Rosin</p><p>etal., 2006) affects the activity of the retrotrapezoid nucleus. In addition, direct inputs come from the</p><p>pre- Bötzinger complex (Tan etal., 2010; Yang and Feldman, 2018), Kölliker- Fuse nucleus, and lateral</p><p>and medial parabrachial nuclei (Rosin etal., 2006; Song etal., 2012a; Lima etal., 2019b), rVRG and</p><p>cVRG (Rosin etal., 2006; Jones etal., 2016), lateral and paraventricular hypothalamus (Rosin etal.,</p><p>2006; Geerling etal., 2010), and central amygdala and periaqueductal gray (Rosin etal., 2006).</p><p>The output of the retrotrapezoid is glutamatergic and affects respiration directly via projections</p><p>to the pre- Bötzinger complex, rVRG and cVRG, as well as to the cervical and thoracic spinal cord</p><p>(Rosin etal., 2006; Bochorishvili etal., 2012; Li etal., 2016; Silva etal., 2016a), and indirectly via</p><p>the Bötzinger complex, Kölliker- Fuse nucleus, lateral parafacial nucleus, NTS, and lateral and medial</p><p>parabrachial nucleus (Rosin etal., 2006; Abbott etal., 2009; Bochorishvili etal., 2012; Silva etal.,</p><p>2016a).</p><p>Nucleus of the solitary tract</p><p>The NTS houses respiratory chemoreceptors (Coates etal., 1993; Nattie and Li, 2002; Nattie and Li,</p><p>2008; Fu etal., 2017), and is the prime recipient of visceral input. Especially the caudal part of the NTS</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 15 of 67</p><p>receives direct input from pulmonary and cardiovascular baro-, chemo- and stretch receptors, as well</p><p>as from chemoreceptors in the carotid bodies (Miura and Reis, 1972; Sant’Ambrogio, 1982; Finley</p><p>and Katz, 1992; Mifflin, 1992; Lee and Yu, 2014; Zoccal etal., 2014; Mazzone and Undem, 2016;</p><p>Umans and Liberles, 2018; Zera etal., 2019; Suarez- Roca etal., 2021; Figure5A–B). These inputs</p><p>allow the NTS to contribute to metabolic homeostasis, affecting not only cardiorespiratory function,</p><p>but also food intake and digestion (Rinaman, 2010; Zoccal etal., 2014). The NTS is not essential for</p><p>inspiration, but NTS dysfunction impairs the response to hypercapnia (Berger and Cooney, 1982;</p><p>Speck and Feldman, 1982; Nattie and Li, 2008; Dean and Putnam, 2010), which could underlie</p><p>congenital central hypoventilation syndrome (Fu etal., 2017). The ventrolateral NTS is also known as</p><p>the dorsal respiratory group (Berger, 1977).</p><p>The NTS contains multiple types of respiratory neurons, some relate to inspiration, others to expi-</p><p>ration or are phase- independent (Backman etal., 1984; Ezure and Tanaka, 2000; Ho etal., 2001;</p><p>Kubin etal., 2006; Subramanian etal., 2007; Figure5D). Among these are neurons, located mainly</p><p>in the commissural and medial NTS, that respond to pulmonary irritant receptors, including RARs and</p><p>C- fibers mediating cough reflexes, and that are suppressed by the pump neurons (P- cells; Berger,</p><p>1977; Kubin etal., 2006; Canning etal., 2014; Mutolo, 2017; Farrell etal., 2020).</p><p>P- cells of the ventrolateral and other parts of the caudal NTS respond to SARs reporting airway</p><p>stretch (Kubin etal., 2006; Zoccal etal., 2014; Mazzone and Undem, 2016; Umans and Liberles,</p><p>2018). The firing rates of the P- cells relate to lung volume, possibly modulated by the respiratory</p><p>rhythm (Berger, 1977; Davies etal., 1987; Bonham and McCrimmon, 1990; Miyazaki etal., 1999).</p><p>Activation of these P- cells results in an inhibition of the rVRG (Ezure and Tanaka, 1996; Zheng etal.,</p><p>1998) and phrenic motor nucleus (Fedorko etal., 1983; Ellenberger etal., 1990b; Boulenguez</p><p>etal., 2007; Lois etal., 2009).</p><p>In addition, the NTS is involved in several other mechanisms controlling respiration. These entail a</p><p>strong and direct projection to the phrenic motor nucleus (Loewy and Burton, 1978; Fedorko etal.,</p><p>1983; Rikard- Bell etal., 1984; Dobbins and Feldman, 1994; Boulenguez etal., 2007; Lois etal.,</p><p>2009). Furthermore, P- cells of the intermediate NTS mediate the Hering- Breuer inspiratory reflex</p><p>that protects the lungs against overinflation (Breuer, 1868; Berger, 1977; Bonham and McCrimmon,</p><p>1990; Kubin etal., 2006; Lee and Yu, 2014; Chang etal., 2015; Nonomura etal., 2017; Umans</p><p>and Liberles, 2018).</p><p>In addition to the extensive visceral inputs, the caudal NTS also receives central input, in particular</p><p>from other regions of the NTS, lateral and paraventricular hypothalamus and central amygdala (Geer-</p><p>ling etal., 2010; Ruyle etal., 2019; Gasparini etal., 2020), but also from the pre- Bötzinger complex</p><p>(Tan etal., 2010; Koshiya etal., 2014; Yang and Feldman, 2018), Bötzinger complex (Merrill etal.,</p><p>1983; Fedorko and Merrill, 1984; Livingston and Berger, 1989; Ezure etal., 2003), rVRG (Yamada</p><p>etal., 1988; Ellenberger et al., 1990a; Zheng etal., 1998), Kölliker- Fuse nucleus (Fulwiler and</p><p>Saper, 1984; Song etal., 2012a; Geerling etal., 2017), retrotrapezoid nucleus (Rosin etal., 2006;</p><p>Bochorishvili et al., 2012), caudal raphe (Brust et al., 2014), bed nucleus of the stria terminalis</p><p>(Gasparini etal., 2020), lateral and medial parabrachial nuclei (Saper and Loewy, 1980; Herbert</p><p>etal., 1990; Bianchi etal., 1998), periaqueductal gray (Chen etal., 2022), spinal trigeminal nucleus</p><p>(Panneton etal., 2006), paratrigeminal nucleus (Saxon and Hopkins, 1998; de Sousa Buck etal.,</p><p>2001; McGovern etal., 2015b; Driessen etal., 2018), as well as from insular and infralimbic areas of</p><p>the cerebral cortex (Gasparini etal., 2020; Figure5C). Evidence for significant projections from the</p><p>cerebellum to the NTS is currently lacking (Teune etal., 2000; Gasparini etal., 2020).</p><p>As mentioned above, strong and direct projections from the NTS to the phrenic nucleus have</p><p>been reported, while the NTS targets also the upper airway motor nuclei (Loewy and Burton, 1978;</p><p>Norgren, 1978; Beckstead etal., 1980; Núñez- Abades etal., 1990; Hayakawa etal., 2000; Kawai,</p><p>2018; Guo et al., 2020). Other target areas are the pre- Bötzinger complex (Yang et al., 2020),</p><p>Bötzinger complex (Gang etal., 1995), PiCo (Oliveira etal., 2021), lateral parafacial nucleus (Bian-</p><p>cardi etal., 2021), cVRG (Loewy and Burton, 1978; Beckstead etal., 1980; Gerrits and Holstege,</p><p>1996), retrotrapezoid nucleus (Rosin etal., 2006; Lima etal., 2019b), locus coeruleus (McGovern</p><p>et</p><p>al., 2015b; Kawai, 2018), dorsal raphe (Peyron etal., 2018), lateral, paraventricular and dorso-</p><p>medial hypothalamus (King etal., 2012; McGovern etal., 2015b; Kawai, 2018), bed nucleus of the</p><p>stria terminalis and central amygdala (Shin etal., 2008; Bienkowski and Rinaman, 2013; McGovern</p><p>et al., 2015b; Ni et al., 2016; Kawai, 2018), lateral and medial parabrachial nuclei (Loewy and</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 16 of 67</p><p>Burton, 1978; Beckstead etal., 1980; Herbert etal., 1990; McGovern etal., 2015b; Hashimoto</p><p>etal., 2018; Kawai, 2018; Yu etal., 2022), periaqueductal gray (Herbert and Saper, 1992; Kawai,</p><p>2018), spinal trigeminal nucleus (Loewy and Burton, 1978; McGovern etal., 2015b), pedunculo-</p><p>pontine tegmental nucleus (PPTg) (Steininger etal., 1992), cerebellum (Batini etal., 1978; Somana</p><p>and Walberg, 1979b; Saigal etal., 1980b; Fu etal., 2011), and inferior olive (Loewy and Burton,</p><p>1978; McGovern etal., 2015b; Figure5C).</p><p>Locus coeruleus</p><p>The locus coeruleus has broad impact on brain activity, affecting among others attention, motivation,</p><p>memory, and the level of arousal through its widespread network of noradrenergic fibers (Schwarz</p><p>etal., 2015; Breton- Provencher and Sur, 2019; Chandler etal., 2019; Poe etal., 2020). The locus</p><p>coeruleus can also mediate sensory- evoked awakenings from sleep (Hayat etal., 2020) and has been</p><p>proposed to be a key center in coupling brain activity with the respiratory cycle (Melnychuk etal.,</p><p>2021).</p><p>Hypercapnia leads to increased activity in the locus coeruleus, which is an evolutionary conserved</p><p>phenomenon observed in amphibians and mammals (Elam et al., 1981; Pineda and Aghajanian,</p><p>1997; Biancardi etal., 2008; Santin and Hartzler, 2013; Quintero etal., 2017). This increase in</p><p>neural activity can lead to stronger basal ventilation (Hilaire etal., 2004; Liu etal., 2021b), although</p><p>this effect was not observed in all studies (Gargaglioni etal., 2010). The impact of the locus coeruleus</p><p>may therefore depend on behavioral or experimental conditions.</p><p>Stimulation of the locus coeruleus can modulate activity in the pre- Bötzinger complex via a direct</p><p>projection (Liu etal., 2021b). The locus coeruleus also targets many other brain regions with three</p><p>diverging pathways, with individual locus coeruleus neurons projecting to functionally related areas</p><p>(Szabadi, 2013; Schwarz etal., 2015; Poe etal., 2020). The ascending pathway targets the thal-</p><p>amus and cerebral cortex, but also the paraventricular and lateral hypothalamus, periaqueductal gray,</p><p>dorsal and caudal raphe nuclei, bed nucleus of the stria terminalis, and central amygdala (Jones and</p><p>Moore, 1977; Jones and Yang, 1985; Hermann etal., 1997; Ni etal., 2016; Borodovitsyna etal.,</p><p>2020). Other targets include the nuclei of the mesodiencephalic junction (MDJ) (Jones and Yang,</p><p>1985). The cerebellar pathway targets both the cerebellar nuclei and cortex (Olson and Fuxe, 1971;</p><p>Saigal etal., 1980a; Nagai etal., 1981; Room etal., 1981; Loughlin etal., 1986; Dietrichs, 1988;</p><p>Fu etal., 2011). The third, descending pathway targets the brainstem and spinal cord, including the</p><p>ambiguus, hypoglossal and facial nuclei, dorsal raphe, and the pedunculopontine tegmental nucleus</p><p>(Jones and Yang, 1985). The spinal projections are, as typical for locus coeruleus projections, wide-</p><p>spread and involve also the phrenic nucleus, without showing a specific concentration of terminals in</p><p>the latter (Bruinstroop etal., 2012).</p><p>In turn, the locus coeruleus receives widespread but relatively sparse projections from the cerebral</p><p>cortex, and denser projections from the hypothalamus, central amygdala, bed nucleus of the stria</p><p>terminalis, raphe nuclei, Kölliker- Fuse nucleus and adjacent parabrachial nuclei, and periaqueductal</p><p>gray (Luppi etal., 1995; Schwarz etal., 2015). There is also input from the pre- Bötzinger complex</p><p>(Yackle et al., 2017), NTS (McGovern et al., 2015b; Kawai, 2018), PPTg (Woolf and Butcher,</p><p>1989), and cerebellar nuclei, in addition to numerous direct projections from cerebellar Purkinje cells</p><p>(Schwarz etal., 2015).</p><p>Raphe nuclei</p><p>The raphe nuclei consist of clusters of neurons along the midline of the midbrain, pons and medulla.</p><p>Of these, the dorsal and caudal raphe both house CO2 chemoreceptors, and together form the main</p><p>source of serotonin in the respiratory system (Wang etal., 2001; Severson etal., 2003; Teran etal.,</p><p>2014; Figure6A). Disturbances in serotonin release have been linked to respiratory dysfunction in</p><p>Prader- Willi syndrome (Matarazzo etal., 2017) as well as to SIDS (Paterson etal., 2006; Kinney and</p><p>Haynes, 2019). The risk of the latter may be increased by prenatal exposure to nicotine that can later</p><p>cause impairments in serotonin release during hypercapnia (Avraam etal., 2020).</p><p>The dorsal raphe nucleus mediates the CO2 arousal reflex via its projection to the lateral parab-</p><p>rachial nucleus (Petrov et al., 1992; Smith et al., 2018; Kaur et al., 2020). Other projections,</p><p>sometimes involving collateral fibers, target predominantly forebrain regions, including the lateral</p><p>hypothalamic nucleus, bed nucleus of the stria terminalis, central amygdala, and vestibular nuclei</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 17 of 67</p><p>Complex spikesC D</p><p>Respiration</p><p>Simple spikes 3�/2</p><p>� 0</p><p>�/2</p><p>50</p><p>0</p><p>(Hz)</p><p>25</p><p>25 Hz</p><p>0</p><p>* *</p><p>-100</p><p>100</p><p>-200</p><p>Control Stim. Control Mutant</p><p>200E</p><p>�I</p><p>nt</p><p>er</p><p>va</p><p>l t</p><p>im</p><p>e</p><p>(m</p><p>s)</p><p>0.24</p><p>0.20</p><p>0.28</p><p>0.16</p><p>0.32F</p><p>C</p><p>V2</p><p>G H</p><p>I J</p><p>G H-J</p><p>A B</p><p>RMg</p><p>Caudal</p><p>raphe</p><p>Dorsal</p><p>raphe</p><p>Cerebellar</p><p>cortex</p><p>Cerebellar</p><p>nuclei</p><p>Rob</p><p>Rpa</p><p>Pre-</p><p>Bötzinger</p><p>complex</p><p>Phrenic</p><p>nucleus</p><p>Locus</p><p>coeruleus</p><p>CO2</p><p>Ambiguus</p><p>nucleus</p><p>Retro-</p><p>trapezoid</p><p>nucleus</p><p>CO2</p><p>Trigeminal</p><p>motor</p><p>nucleus</p><p>NTS</p><p>CO2</p><p>Hypo-</p><p>glossal</p><p>nucleus</p><p>Caudal</p><p>raphe</p><p>Other</p><p>5-HTNon-5-HT</p><p>CO2</p><p>Raphe</p><p>magnus</p><p>Egr2-Pet1</p><p>Raphe</p><p>obscurus</p><p>Tac-Pet1</p><p>CO2</p><p>CO2</p><p>Lateral</p><p>hypo-</p><p>thalamus</p><p>Vestibular</p><p>nuclei</p><p>Inferior</p><p>olive</p><p>Reticular</p><p>formation MDJ</p><p>Spinal</p><p>trigeminal</p><p>nucleus</p><p>Thoracic</p><p>spinal</p><p>cord</p><p>Facial</p><p>nucleus</p><p>Lateral</p><p>parafacial</p><p>nucleus</p><p>Kölliker-</p><p>Fuse</p><p>nucleus</p><p>PPTgMPBN</p><p>Basal</p><p>pons</p><p>Central</p><p>amygdala BNST</p><p>Peri-</p><p>aqueductal</p><p>gray</p><p>LPBN</p><p>Paraventri-</p><p>cular</p><p>hypothal.</p><p>Figure 6. Raphe nuclei and cerebellum. (A) The caudal raphe consists of the raphe magnus (RMg), the raphe obscurus (Rob) and the raphe pallidus</p><p>(Rpa). The cerebellum consists of the cerebellar cortex and the cerebellar nuclei. (B) Different populations of raphe neurons can have different projection</p><p>patterns. For example, Egr2- positive serotonergic neurons of RMg have intrinsic chemoreceptor properties and project mainly to other central</p><p>chemoreceptor areas. The downstream Tac- positive serotonergic neurons of Rob lack intrinsic chemoreceptor properties and project predominantly</p><p>to respiratory motor neurons. Other neurons of the caudal raphe, whether serotonergic or non- serotonergic, extend the caudal raphe projections to</p><p>further respiratory regions. These projections partially overlap with those of the dorsal raphe. Indicated are also the projections from the cerebellar</p><p>nuclei. Note that also the locus coeruleus receives cerebellar input via direct Purkinje cells projections. (C) At rest, Purkinje cells of the lateral cerebellum</p><p>can show modulation of their complex spike and simple spike frequency in relation to the respiratory cycle. This is illustrated with a representative</p><p>electrophysiological recording of a Purkinje cell in an awake mouse. Complex spikes are noted with a red dot on top of the trace. In this example,</p><p>Figure 6 continued on next page</p><p>https://doi.org/10.7554/eLife.83654</p><p>Review article Neuroscience</p><p>Krohn etal. eLife 2023;12:e83654. DOI: https://doi.org/10.7554/eLife.83654 18 of 67</p><p>(Vertes, 1991; Petrov etal., 1992; Halberstadt and Balaban, 2006; Vasudeva et</p>